Submissions for variant NM_014000.3(VCL):c.1907A>G (p.His636Arg)

gnomAD frequency: 0.00240  dbSNP: rs71579374

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172736	SCV000051359	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038810	SCV000062488	likely benign	not specified	2016-01-22	criteria provided, single submitter	clinical testing	p.His636Arg in exon 14 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 0.67% (44/6604) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs71579374).
GeneDx	RCV000172736	SCV000236471	likely benign	not provided	2020-11-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 25016126, 25351510, 26656175, 23396983, 24503780, 20474083, 27930701)
Blueprint Genetics	RCV000208305	SCV000264316	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-12-11	criteria provided, single submitter	clinical testing
Invitae	RCV001084130	SCV000289910	benign	Dilated cardiomyopathy 1W	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000252819	SCV000318533	likely benign	Cardiovascular phenotype	2019-04-12	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.
CeGaT Center for Human Genetics Tuebingen	RCV000172736	SCV001147979	benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	VCL: BS1, BS2
Illumina Laboratory Services, Illumina	RCV001084130	SCV001266157	uncertain significance	Dilated cardiomyopathy 1W	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038810	SCV001337887	benign	not specified	2020-01-06	criteria provided, single submitter	clinical testing	Variant summary: VCL c.1907A>G (p.His636Arg) 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 0.0014 in 252006 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 31 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.1907A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Zimmerman_2010). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At least one co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1090+1G>A, LOVD database citing Lopes_2013), providing supporting evidence for a benign role.Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x benign, 2x likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign.
Genetics and Genomics Program, Sidra Medicine	RCV001293168	SCV001434165	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003964863	SCV004782867	likely benign	VCL-related disorder	2019-10-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172736	SCV001741676	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038810	SCV001919242	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172736	SCV001932841	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172736	SCV001954464	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172736	SCV001972251	likely benign	not provided		no assertion criteria provided	clinical testing