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

gnomAD frequency: 0.00218  dbSNP: rs146951171

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	RCV000079432	SCV000196826	likely benign	not provided	2020-12-16	criteria provided, single submitter	clinical testing
Invitae	RCV001080549	SCV000285817	likely benign	Walker-Warburg congenital muscular dystrophy	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528283	SCV000311565	benign	FKTN-related disorder	2019-08-12	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV000241990	SCV000320317	likely benign	Cardiovascular phenotype	2019-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001167248	SCV001329718	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000079432	SCV001800229	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079432	SCV001966039	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001080549	SCV002078748	benign	Walker-Warburg congenital muscular dystrophy	2019-10-21	no assertion criteria provided	clinical testing