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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.310 | MRPL50 |
Anna Ritchie gene: MRPL50 was added gene: MRPL50 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: MRPL50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPL50 were set to PMID: 37148394 Phenotypes for gene: MRPL50 were set to Mitochondrial disease, MONDO: 004470, MRPL50-related Review for gene: MRPL50 was set to AMBER Added comment: A homozygous missense variant (c.335T>A; p.Val112Asp) shared by twin sisters presenting with premature ovarian insufficiency, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction. Quantitative proteomics data demonstrated a significant reduction in abundance of MRPL50 protein when compared with controls. Patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. This data supports a biochemical phenotype associated with MRPL50 variants. Knockdown/knockout of mRpL50 in Drosophila, resulted abnormal ovarian development. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.307 | MRPS7 |
Elena Tucker gene: MRPS7 was added gene: MRPS7 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: MRPS7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MRPS7 were set to PMID: 25556185; 36421788 Phenotypes for gene: MRPS7 were set to sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency Review for gene: MRPS7 was set to AMBER Added comment: The initial report (PMID: 25556185) describes a homozygous missense variant in two sisters with sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. One sister died in early adolescence but the other survived beyond puberty and had primary ovarian insufficiency. Experimental evidence supported causation of the MRPS7 variant. The second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.302 | CCDC155 |
Melanie Marty gene: CCDC155 was added gene: CCDC155 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: CCDC155 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC155 were set to 35674372; 35708642; 29790874; 35587281 Phenotypes for gene: CCDC155 were set to Non-obstructive azoospermia; Premature ovarian insufficiency; Infertility disorder, MONDO:0005047, CCDC155-related Review for gene: CCDC155 was set to GREEN Added comment: Current HGNC name is KASH5 Summary: 4 families reported with non-obstructive azoospermia or premature ovarian insufficiency. Functional studies have been performed and mouse models recapitulate the phenotype. PMID: 35674372 CNV and frameshift variants in KASH5 were identified in a non-obstructive azoospermia affected patient and in his infertile sister by whole-exome sequencing and CNV array. Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis. PMID: 35708642 Hom splice identified in KASH5 in 2 sisters with premature ovarian insufficiency. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes. PMID: 29790874 2 brothers with non-obstructive azoospermia with hom missense in CCDC155 PMID: 35587281 2 siblings with hom missense in CCDC155 non-obstructive azoospermia and premature ovarian insufficiency. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.274 | XRCC4 |
Bryony Thompson gene: XRCC4 was added gene: XRCC4 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: XRCC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: XRCC4 were set to 25742519; 34794894 Phenotypes for gene: XRCC4 were set to Short stature, microcephaly, and endocrine dysfunction MIM#616541 Review for gene: XRCC4 was set to RED Added comment: A single female case with a homozygous variant has been reported with hypogonadism as a feature of the condition. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.267 | BLM |
Bryony Thompson gene: BLM was added gene: BLM was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BLM were set to 34794894; 29056561; 28846287 Phenotypes for gene: BLM were set to Bloom syndrome MIM#210900 Review for gene: BLM was set to GREEN gene: BLM was marked as current diagnostic Added comment: Hypogonadism and premature menopause are reported features of the condition Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.265 | WRN |
Bryony Thompson gene: WRN was added gene: WRN was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: WRN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WRN were set to 34794894; 20301687 Phenotypes for gene: WRN were set to Werner syndrome MIM#277700 Review for gene: WRN was set to GREEN gene: WRN was marked as current diagnostic Added comment: Hypogonadism is a prominent feature of the condition, reportedly present in ~80% of cases. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.251 | FANCL |
Bryony Thompson changed review comment from: 2 independent cases reported with heterozygous loss of function variants and primary ovarian insufficiency. However, there is no reported evidence of POI in female carriers of FANCL pathogenic variants for fanconi anemia. Null mouse model is less fertile and has defective proliferation of germ cells. Sources: Literature; to: 2 independent cases reported with heterozygous loss of function variants and primary ovarian insufficiency. Also, homozygous frameshift insertion identified in a POI case without any known features of fanconi anaemia. Null mouse model is less fertile and has defective proliferation of germ cells. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.247 | FANCA |
Bryony Thompson changed review comment from: PMID: 33025164 - a mouse model heterozygous for a hypomorphic variant (c.3581del9, p.QEA1194-1196del) had impaired follicle development and sub-fertility. PMID: 32962729 - a POI case heterozygous for a rare missense variant (p.H780Q) PMID: 31535215 - 2 unrelated Chinese POI cases with 2 different rare missense variants (p.R591Q, 42 hets in gnomAD v2.1 & p.E1296G), both with supporting in vitro functional assays. Also, a heterozygous loss of function (Fanca+/-) mouse model showed reduced fertility and declined numbers of follicles with aging PMID: 10915769 - female knockout mice demonstrate hypogonadism and infertility Sources: Literature; to: PMID: 33025164 - a mouse model heterozygous for a hypomorphic variant (c.3581del9, p.QEA1194-1196del) had impaired follicle development and sub-fertility. PMID: 32962729 - a POI case heterozygous for a rare missense variant (p.H780Q) PMID: 31535215 - 2 unrelated Chinese POI cases with 2 different rare missense variants (p.R591Q, 42 hets in gnomAD v2.1 & p.E1296G), both with supporting in vitro functional assays. Also, a heterozygous loss of function (Fanca+/-) mouse model showed reduced fertility and declined numbers of follicles with aging PMID: 10915769 - female knockout mice demonstrate hypogonadism and infertility Hypergonadotropic hypogonadism is listed as an endocrine feature of the Fanconi anaemia phenotype in OMIM. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.246 | FANCA |
Bryony Thompson gene: FANCA was added gene: FANCA was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: FANCA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FANCA were set to 34794894; 33025164; 31535215; 10915769 Phenotypes for gene: FANCA were set to Primary ovarian insufficiency Review for gene: FANCA was set to AMBER Added comment: PMID: 33025164 - a mouse model heterozygous for a hypomorphic variant (c.3581del9, p.QEA1194-1196del) had impaired follicle development and sub-fertility. PMID: 32962729 - a POI case heterozygous for a rare missense variant (p.H780Q) PMID: 31535215 - 2 unrelated Chinese POI cases with 2 different rare missense variants (p.R591Q, 42 hets in gnomAD v2.1 & p.E1296G), both with supporting in vitro functional assays. Also, a heterozygous loss of function (Fanca+/-) mouse model showed reduced fertility and declined numbers of follicles with aging PMID: 10915769 - female knockout mice demonstrate hypogonadism and infertility Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.244 | DMC1 |
Bryony Thompson gene: DMC1 was added gene: DMC1 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: DMC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DMC1 were set to 34794894; 29331980; 9660954; 9660953 Phenotypes for gene: DMC1 were set to Primary ovarian insufficiency; non-obstructive azoospermia Review for gene: DMC1 was set to AMBER Added comment: 1 case with POI and 1 family with diminished ovarian reserve rather than POI, and a supporting mouse model PMID: 34515795 - a homozygous frameshift (p. Glu10Asnfs*31) cosegregated with non-obstructive azoospermia in 1 brother and diminished ovarian reserve (not primary ovarian insufficiency) in 2 sisters in a non-consanguineous family. PMID: 29331980 - a homozygous missense (p.Asp36Asn) cosegregated with non-obstructive azoospermia and POI phenotypes in a single family. PMID: 18166824 - a POI case identified with a homozygous missense (p.Met200Val, 185 homozygotes in gnomAD v2.1), which is too common for a recessive Mendelian disease PMID: 9660954, 9660953 - both male and female knockout mice are sterile. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.241 | CPEB1 |
Bryony Thompson gene: CPEB1 was added gene: CPEB1 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature SV/CNV tags were added to gene: CPEB1. Mode of inheritance for gene: CPEB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CPEB1 were set to 34794894; 33095795; 32354341; 30689869; 11702780 Phenotypes for gene: CPEB1 were set to Primary ovarian insufficiency Review for gene: CPEB1 was set to AMBER Added comment: Large CNVs including CPEB1 mainly reported, but also include BNC1. PMID: 33095795 - 1 POI case with missense variant p.R87C, which has 101 hets in gnomAD v2.1 (too common for a Mendelian dominantly inherited disease). Also another POI case with an 83.8Kb deletion including CPEB1. PMID: 32354341 - 1 primary amenorrhea case heterozygous deletion of exons 8-12 of CPEB1 PMID: 30689869 - 6 POI cases (including previously reported) with a 15q25.2 deletion including CPEB1, but also including POI gene BNC1. Also, a homozygous microdeletion involving CPEB1 intron 1 in one case. PMID: 11702780 - knockout mouse model had vestigial ovaries devoid of oocytes Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.239 | BRCA2 |
Bryony Thompson gene: BRCA2 was added gene: BRCA2 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: BRCA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BRCA2 were set to 34794894; 30207912; 30865812 Phenotypes for gene: BRCA2 were set to Fanconi anemia, complementation group D1 MIM#605724; premature ovarian failure Review for gene: BRCA2 was set to GREEN Added comment: 5 cases from 4 families with biallelic variants and POI PMID: 30207912 - 2 sisters with biallelic variants and ovarian dysgenesis as a feature of the condition. Also, supporting Drosophila model. PMID: 30865812 - premature ovarian insufficiency present in 2 unrelated cases with biallelic variants PMID: 32482800 - a homozygous hypomorphic BRCA2 variant in a patient with POI without cancer or FA Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.235 | BNC1 |
Bryony Thompson gene: BNC1 was added gene: BNC1 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: BNC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BNC1 were set to 34794894; 30010909; 16624857; 32962729, 32894148 Phenotypes for gene: BNC1 were set to Premature ovarian failure 16 MIM#618723 Review for gene: BNC1 was set to GREEN Added comment: PMID: 30010909 - a heterozygous frameshift variant segregates with POF in 6 affected females in a Chinese family. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility. PMID: 32962729 - 1 POF case with p.Asp575Val (which has 89 hets in gnomAD v2.1) and 1 POF case with biallelic missense variants (p.Asp568Val & p.Leu525Pro). SCV001364363.1 - 1 POF case submitted by Medical Cytogenetics and Molecular Genetics Laboratory,IRCCS Istituto Auxologico Italiano to ClinVar with NM_001717.4(BNC1):c.2273C>T (p.Thr758Ile) PMID: 32894148, 30689869, 27301361 - large CNVs involving BNC1 reported in POF cases PMID: 16624857 - knockdown of the gene in mouse oocytes lead to subfertility Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.228 | BMPR1A |
Bryony Thompson gene: BMPR1A was added gene: BMPR1A was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: BMPR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMPR1A were set to 28505269; 34794894; 31769494; 20363875 Phenotypes for gene: BMPR1A were set to Primary ovarian insufficiency Review for gene: BMPR1A was set to AMBER Added comment: Two POI cases reported with 2 different missense variants (p.Arg442His, p.Tyr425Cys). Arg442His has supporting in vitro functional evidence. Bmpr1a conditional knockout female mice are subfertile with reduced spontaneous ovulation. No POI reported in association with juvenile polyposis syndrome, which is caused by heterozygous variants in BMPR1A. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.224 | NOTCH2 |
Bryony Thompson gene: NOTCH2 was added gene: NOTCH2 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: NOTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NOTCH2 were set to 34794894; 32772338; 32312275; 30304577; 28505269; 28283672 Phenotypes for gene: NOTCH2 were set to Primary ovarian insufficiency Review for gene: NOTCH2 was set to GREEN Added comment: At least 4 missense (in 5 women) with suggestive loss of function mechanisms and supporting mouse models PMID: 32772338 - variable Hajdu-Cheney syndrome phenotype in family. Affected daughter with truncating variant not expected to cause NMD (pTrp2253Ter) had hypothalamic hypogonadism as a feature of the condition, but mother did not. PMID: 32312275 - mother and daughter in a POI pedigree were both heterozygous for the missense p.Asp1853His (6 hets in gnomAD v2.1). In vitro functional assays of the variant demonstrated that it wasn't an activating mutation. PMID: 30304577, 28505269 - 4 unrelated women with POI heterozygous for missense variants (p.Ser1804Leu, p.Gln1811His, p.Leu2408His, p.Pro2359Ala) and 1 woman suspected biallelic (p.Ala2316Val & p.Leu2408His). In vitro luciferase reporter assays in KGN cells demonstrated reduced function for S1804L (15% less), A2316V (27% less), and P2359A (14% less), the other missense were similar to WT. Additionally, p.Leu2408His has 583 hets in gnomAD v2.1. Suggested that POI is associated with loss of function, rather than the gain of function variants that cause Hajdu-Cheney syndrome and Alagille syndrome. PMID: 28283672 - supporting conditional knockout mouse models Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.223 | LHX8 |
Bryony Thompson gene: LHX8 was added gene: LHX8 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: LHX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LHX8 were set to 34794894; 34095689; 29329412; 27603904 Phenotypes for gene: LHX8 were set to Primary ovarian insufficiency Review for gene: LHX8 was set to RED Added comment: Only supporting mouse model. Same variant reported in 2 cases is too common PMID: 34095689 - 1 POI case with missense p.Ala325Val, which has 533 hets and 22 homozygotes in gnomAD v2.1, too common for Mendelian disease PMID: 29329412 - Lhx8 knockout mouse model demonstrates premature depletion of oocytes PMID: 27603904 - 1 POI case also with p.Ala325Val Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.219 | DAZL |
Bryony Thompson gene: DAZL was added gene: DAZL was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: DAZL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DAZL were set to 34794894; 33095795; 16884537; 9288969 Phenotypes for gene: DAZL were set to Primary ovarian insufficiency Review for gene: DAZL was set to AMBER Added comment: PMID: 33095795 - Single POI case with heterozygous stopgain (c.640C>T:p.Q214*). PMID: 16884537 - 4 heterozygous unrelated early menopause/POI cases with heterozygous missense (all rare in gnomAD v2.1, except p.Asn10His which has 14 hets) PMID: 9288969 - supporting knockout mouse model Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.217 | ATG9A |
Bryony Thompson gene: ATG9A was added gene: ATG9A was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: ATG9A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATG9A were set to 34794894; 30224786 Phenotypes for gene: ATG9A were set to Primary ovarian insufficiency Review for gene: ATG9A was set to RED Added comment: Single heterozygous case reported, with in vitro functional assay supporting a loss of function mechanism for the missense variant. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.215 | ATG7 |
Bryony Thompson gene: ATG7 was added gene: ATG7 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: ATG7 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ATG7 were set to 34794894; 34161705; 30224786; 25590799 Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, autosomal recessive 31 MIM#619422; primary ovarian insufficiency Review for gene: ATG7 was set to AMBER Added comment: PMID: 30224786 - a heterozygous missense (p.Phe403Leu) in a single proband with POI and in vitro functional assays supporting loss of function for the variant. PMID: 34161705 - one family with biallelic variants and SCAR31 had late-onset or no puberty, and another patient with SCAR31 from another family presented with hypogonadotropic hypogonadism and gynecomastia (2/5 families reported with endocrine features). PMID: 25590799 - germ cell-specific mouse Atg7 knockout recapitulates the human POI phenotype Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.213 | GATA4 |
Bryony Thompson gene: GATA4 was added gene: GATA4 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: GATA4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: GATA4 were set to 34794894; 33095795; 29544631 Phenotypes for gene: GATA4 were set to Primary ovarian insufficiency; congenital heart defect Review for gene: GATA4 was set to AMBER Added comment: One woman with a homozygous missense (p.Pro407Arg) and POI, sensorineural deafness, congenital heart defect, and kidney insufficiency. Another woman with a heterozygous missense variant (p.Ala94Thr) with secondary amenorrhea (but no mention of congenital heart defects). Also, supporting mouse models for a role for GATA4 in ovarian development. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.206 | PREPL |
Bryony Thompson gene: PREPL was added gene: PREPL was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: PREPL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PREPL were set to 34794894; 28726805; 30924587; 32218803 Phenotypes for gene: PREPL were set to Hypotonia-cystinuria syndrome; premature ovarian failure Review for gene: PREPL was set to GREEN Added comment: At least 5 unrelated cases reported with hypergonadotrophic hypogonadism or absence of the ovaries as a feature of the condition. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.202 | POLR2C |
Bryony Thompson gene: POLR2C was added gene: POLR2C was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: POLR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POLR2C were set to 34794894; 29367954 Phenotypes for gene: POLR2C were set to Primary ovarian insufficiency Review for gene: POLR2C was set to AMBER Added comment: One family with POI segregating a nonsense variant (p.Lys152Ter) and a case with sporadic POI with a splice region variant (c.206-3C>T). Knockdown of the gene in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation. Two missense in premature ovarian failure cases submitted to ClinVar by Shandong Provincial Hospital Affiliated to Shandong University (SCV001877131.1, SCV001877153.1). Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.200 | KHDRBS1 |
Bryony Thompson gene: KHDRBS1 was added gene: KHDRBS1 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: KHDRBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KHDRBS1 were set to 34794894; 29808484; 28938739; 20881015 Phenotypes for gene: KHDRBS1 were set to Premature ovarian failure Review for gene: KHDRBS1 was set to GREEN Added comment: 4 cases in 3 unrelated families and a supporting mouse model PMID: 28938739 - missense (c.460A > G, p.M154V) identified in a Chinese mother and daughter with POI, and another missense (c.263C > T, p.P88L) identified in an idiopathic POI case. SCV001364312.1 - case with POI and missense (p.Pro421Leu) submitted by an Italian institute (ClinVar ID: 929733) PMID: 29808484 - missense (p.Pro296Leu) identified in a POI case, which also has a heterozygous missense in FGFR2. There are 12 hets with Pro296Leu in gnomAD v2.1. This case is not included in the final case count. PMID: 20881015 - supporting null mouse model. Female mice were subfertile. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.197 | ANTXR1 |
Bryony Thompson gene: ANTXR1 was added gene: ANTXR1 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature Mode of inheritance for gene: ANTXR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ANTXR1 were set to 34794894; 27426988; 16272061; 2248288; 17262136 Phenotypes for gene: ANTXR1 were set to GAPO syndrome MIM#230740 Review for gene: ANTXR1 was set to RED Added comment: Premature ovarian insufficiency has been reported in at least 5 cases with GAPO syndrome from 4 families, but only one individual had been genetically confirmed to have an ANTXR1 pathogenic variant. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.191 | HSF2BP |
Zornitza Stark gene: HSF2BP was added gene: HSF2BP was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Expert list Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HSF2BP were set to 32845237 Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245 Review for gene: HSF2BP was set to RED Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters. Sources: Expert list |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.186 | XRCC2 |
Zornitza Stark gene: XRCC2 was added gene: XRCC2 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Expert list Mode of inheritance for gene: XRCC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: XRCC2 were set to 30489636; 30042186 Phenotypes for gene: XRCC2 were set to Premature ovarian failure 17, MIM# 619146; Spermatogenic failure, MIM# 619145 Review for gene: XRCC2 was set to RED Added comment: One individual reported with POF and bi-allelic variants in her gene. Her brother had spermatogenic failure, and one additional family reported with spermatogenic failure. Sources: Expert list |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.183 | POR | Zornitza Stark Marked gene: POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.183 | POR | Zornitza Stark Gene: por has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.183 | POR | Zornitza Stark Phenotypes for gene: POR were changed from to Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.182 | POR | Zornitza Stark Publications for gene: POR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.181 | POR | Zornitza Stark Mode of inheritance for gene: POR was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.180 | POR | Zornitza Stark reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: None; Publications: 32242900; Phenotypes: Disordered steroidogenesis due to cytochrome P450 oxidoreductase, MIM#613571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.156 | AIRE | Zornitza Stark changed review comment from: Hypogonadism is a feature.; to: Hypogonadism is a feature. Multiple families with bi-allelic variants reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.100 | GDF9 | Bryony Thompson edited their review of gene: GDF9: Added comment: PMID: 33036707 - Additional compound het case with primary amenorrhea and was diagnosed with non-syndromic POI and supporting functional assays.; Changed rating: GREEN; Changed publications: 29044499, 8849725, 33036707 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.90 | ZP2 |
Zornitza Stark changed review comment from: Three unrelated individuals reported with bi-allelic variants in this gene and thin zona pellucida. Sources: Literature; to: Three unrelated individuals reported with bi-allelic variants in this gene and thin zona pellucida. Presents with primary infertility rather than POI/POF. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.49 | PEX6 |
Zornitza Stark gene: PEX6 was added gene: PEX6 was added to Amenorrhoea. Sources: Literature Mode of inheritance for gene: PEX6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PEX6 were set to 32399598 Phenotypes for gene: PEX6 were set to Perrault syndrome Review for gene: PEX6 was set to RED Added comment: Well established gene-disease association for peroxisomal disorders, including milder end of the spectrum (Heimler syndrome). Single case report of Perrault syndrome as presenting phenotype. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.47 | BUB1B |
Zornitza Stark gene: BUB1B was added gene: BUB1B was added to Amenorrhoea. Sources: Literature Mode of inheritance for gene: BUB1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BUB1B were set to 32716490 Phenotypes for gene: BUB1B were set to Premature ovarian failure Review for gene: BUB1B was set to AMBER Added comment: There is a well established association between bi-allelic variants and mosaic variegated aneuploidy syndrome, MIM#257300 PMID: 32716490 - Chen et al 2020 - report 2 cases of heterogyzous variants in BUB1B in patients with premature ovarian insufficiency. In the familial case a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all affected individuals. A novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) was found in one of 200 sporadic POI cases and was found to be paternal in origin. In a mouse model with a loss-of-function mutant of Bub1b, Bub1b+/− female mice presented late-onset subfertility. Complete loss of Bub1b caused embryonic lethality in mice.. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.45 | CCDC141 |
Bryony Thompson gene: CCDC141 was added gene: CCDC141 was added to Amenorrhoea. Sources: Literature Mode of inheritance for gene: CCDC141 was set to Unknown Publications for gene: CCDC141 were set to 27014940; 28324054; 25192046 Phenotypes for gene: CCDC141 were set to Anosmic hypogonadotropic hypogonadism Review for gene: CCDC141 was set to AMBER Added comment: A consanguineous family had a homozygous nonsense variant, but also had a homozygous missense in FEZF1. 3 other families reported with heterozygous variants, but other variants in other genes present. In an olfactory mouse model, Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.37 | IGSF10 |
Bryony Thompson gene: IGSF10 was added gene: IGSF10 was added to Amenorrhoea. Sources: Literature Mode of inheritance for gene: IGSF10 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: IGSF10 were set to 27137492; 31042289 Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism Review for gene: IGSF10 was set to AMBER Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.32 | NOBOX |
Ee Ming Wong changed review comment from: - Missense and PTC variants have been identified in > 3 unrelated women diagnosed with POI from different studies - The vast majority of variants are heterozygous, with only one homozygous variant reported in 1 individual with primary amenorrhea and serum FSH level significantly exceeding the threshold value (PMID: 27836978) - Loss of Function has been clearly demonstrated, while dominant negative effect has also been suggested although there is currently limited evidence (PMID: 17701902) - Individuals carrying the same variant can have heterogeneous clinical presentations; to: - Missense and PTC variants have been identified in > 3 unrelated women diagnosed with POI from different studies - The vast majority of variants are heterozygous, with limited reports of homozygous variants (PMID: 27836978; 29067606) - Loss of Function has been clearly demonstrated, while dominant negative effect has also been suggested although there is currently limited evidence (PMID: 17701902) - Individuals carrying the same variant can have heterogeneous clinical presentations |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.32 | FANCL |
Bryony Thompson gene: FANCL was added gene: FANCL was added to Amenorrhoea. Sources: Literature Mode of inheritance for gene: FANCL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FANCL were set to 32048394; 32851770; 11823446 Phenotypes for gene: FANCL were set to Primary ovarian insufficiency Review for gene: FANCL was set to AMBER Added comment: 2 independent cases reported with heterozygous loss of function variants and primary ovarian insufficiency. However, there is no reported evidence of POI in female carriers of FANCL pathogenic variants for fanconi anemia. Null mouse model is less fertile and has defective proliferation of germ cells. Sources: Literature |
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| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.15 | ERCC6 | Bryony Thompson Added comment: Comment on list classification: Strong segregation in one family and supporting functional assays. POI has not been mentioned in carriers for Cockayne syndrome. More evidence is required to determine whether dominant POI associated variants in this gene are specific to the exon expressed in the alternate transcript. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.14 | ERCC6 | Bryony Thompson Added comment: Comment on list classification: Strong segregation in one family and supporting functional assays. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Ovarian Insufficiency_Premature Ovarian Failure v0.0 | POR |
Bryony Thompson gene: POR was added gene: POR was added to Amenorrhoea. Sources: Royal Melbourne Hospital,Expert Review Green Mode of inheritance for gene: POR was set to |
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