ClinVar Miner

Submissions for variant NM_000143.3(FH):c.77C>T (p.Pro26Leu) (rs187226800)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121090 SCV000251414 benign not specified 2014-07-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000227292 SCV000283679 benign Fumarase deficiency 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000121090 SCV000302644 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000392281 SCV000356733 benign Hereditary leiomyomatosis and renal cell cancer 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000310688 SCV000356734 likely benign Multiple Cutaneous and Uterine Leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000227292 SCV000356735 benign Fumarase deficiency 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics RCV000570367 SCV000664486 benign Hereditary cancer-predisposing syndrome 2015-09-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification;Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Integrated Genetics/Laboratory Corporation of America RCV000121090 SCV001372374 benign not specified 2020-06-16 criteria provided, single submitter clinical testing Variant summary: FH c.77C>T (p.Pro26Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 145660 control chromosomes, predominantly at a frequency of 0.028 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11200 fold of the estimated maximal expected allele frequency for a pathogenic variant in FH causing Hereditary Leiomyomatosis and Renal Cell Cancer phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.77C>T has been reported in the literature (e.g. Pan_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
ITMI RCV000121090 SCV000085258 not provided not specified 2013-09-19 no assertion provided reference population

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