ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.3785C>G (p.Thr1262Arg)

gnomAD frequency: 0.00276  dbSNP: rs78488552
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000122293 SCV000229532 benign not specified 2017-03-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000231281 SCV000285569 benign Werner syndrome 2024-01-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000231281 SCV000473354 uncertain significance Werner syndrome 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mendelics RCV000231281 SCV001137603 likely benign Werner syndrome 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000858031 SCV001155404 likely benign not provided 2024-05-01 criteria provided, single submitter clinical testing WRN: BP1, BS1
GeneDx RCV000858031 SCV001795855 likely benign not provided 2021-04-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23891399, 26546047, 27153395, 24728327)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000858031 SCV002011291 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000122293 SCV002071498 likely benign not specified 2021-10-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122293 SCV002103546 benign not specified 2022-02-26 criteria provided, single submitter clinical testing Variant summary: WRN c.3785C>G (p.Thr1262Arg) results in a non-conservative amino acid change located in the Helicase Helix-turn-helix domain (IPR029491) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251350 control chromosomes, predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.3785C>G in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000858031 SCV005409433 uncertain significance not provided 2023-09-13 criteria provided, single submitter clinical testing
ITMI RCV000122293 SCV000086520 not provided not specified 2013-09-19 no assertion provided reference population

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