ClinVar Miner

Submissions for variant NM_000143.3(FH):c.53C>T (p.Pro18Leu) (rs201887750)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756164 SCV000883890 likely benign not provided 2017-11-21 criteria provided, single submitter clinical testing The p.Pro18Leu variant (rs201887750) has been identified in both cases and controls in a cohort of patients diagnosed with uterine leiomyoma (Aissani 2015). The p.Pro18Leu variant is also listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 2.13% in the African population (identified in 329 out of 15,470 chromosomes with 2 homozygotes), and is classified as benign/likely benign in ClinVar (Variant ID: 134413). The proline at codon 18 is weakly conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does not affect the structure/function of the FH protein (SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). Therefore, based on the available evidence, the p.Pro18Leu variant is classified as likely benign.
Ambry Genetics RCV000493989 SCV000581637 benign Hereditary cancer-predisposing syndrome 2015-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000121088 SCV000168545 benign not specified 2013-12-26 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.
ITMI RCV000121088 SCV000085256 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000273634 SCV000356739 likely benign Fumarase deficiency 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000331003 SCV000356740 likely benign Multiple cutaneous leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000373913 SCV000356741 likely benign Multiple Cutaneous and Uterine Leiomyomas 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121088 SCV000917376 benign not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: FH c.53C>T (p.Pro18Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 171230 control chromosomes, predominantly at a frequency of 0.021 within the African subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 8400-folds higher than 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 African origin. To our knowledge, no occurrence of c.53C>T in individuals affected with Hereditary Leiomyomatosis and Renal Cell Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000273634 SCV000556448 benign Fumarase deficiency 2018-01-04 criteria provided, single submitter clinical testing

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