ClinVar Miner

Submissions for variant NM_001079802.2(FKTN):c.167G>A (p.Arg56His) (rs146951171)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000245908 SCV000111311 likely benign not specified 2016-02-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000079432 SCV000151169 uncertain significance not provided 2014-02-03 criteria provided, single submitter clinical testing
GeneDx RCV000245908 SCV000196826 likely benign not specified 2017-08-23 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 RCV001080549 SCV000285817 likely benign Walker-Warburg congenital muscular dystrophy 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000245908 SCV000311565 likely benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000241990 SCV000320317 likely benign Cardiovascular phenotype 2019-04-03 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other data supporting benign classification
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000853033 SCV000995790 benign Hypertrophic cardiomyopathy 2017-02-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000245908 SCV001160417 likely benign not specified 2019-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001167247 SCV001329717 uncertain significance Dilated cardiomyopathy 1X 2018-01-12 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.
Illumina Clinical Services Laboratory,Illumina RCV001167248 SCV001329718 uncertain significance Fukuyama congenital muscular dystrophy 2018-01-12 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.
Integrated Genetics/Laboratory Corporation of America RCV000245908 SCV001361297 likely benign not specified 2019-08-26 criteria provided, single submitter clinical testing Variant summary: FKTN c.167G>A (p.Arg56His) 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 0.00053 in 245444 control chromosomes, predominantly at a frequency of 0.007 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold the estimated maximal expected allele frequency for a pathogenic variant in FKTN causing Cardiomyopathy phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Co-occurrence with another likely pathogenic variant has been reported (TTN c.34782_34785delTTGT, p.C11595fs*9- internal sample), providing supporting evidence for a benign role. To our knowledge, there are no reports of c.167G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function in the literature. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and 5/6 laboratories cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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