Submissions for variant NM_014000.3(VCL):c.1555A>C (p.Ile519Leu)

gnomAD frequency: 0.00064  dbSNP: rs141033098

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172735	SCV000051509	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038798	SCV000062476	benign	not specified	2018-04-06	criteria provided, single submitter	clinical testing	The p.Ile519Leu variant in VCL is classified as benign because it has been ident ified in 0.1% (151/126708) of European chromosomes by the Genome Aggreagation Da tabase (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs141033098). ACMG/AMP Criteria applied: BA1.
GeneDx	RCV000172735	SCV000236469	likely benign	not provided	2021-07-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26191084, 23396983)
Ambry Genetics	RCV000253868	SCV000320414	likely benign	Cardiovascular phenotype	2018-11-08	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.
Invitae	RCV001081141	SCV000559720	likely benign	Dilated cardiomyopathy 1W	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038798	SCV000699356	benign	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: VCL c.1555A>C (p.Ile519Leu) results in a 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 0.00073 in 253200 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 48 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant has been reported in the literature, without strong evidence for causality (Lopes_2013, Pugh_2014), and in one case was reported to co-occur with a truncating DSC2 variant and an in-frame deletion in MYBPC3 (Lopes_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=5) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000172735	SCV000707823	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624752	SCV000740397	uncertain significance	Primary familial dilated cardiomyopathy	2017-03-30	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852616	SCV000995319	likely benign	Ventricular tachycardia	2019-05-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081141	SCV001263795	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000157581	SCV001333793	benign	Cardiomyopathy	2020-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172735	SCV004126794	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	VCL: BS1
Blueprint Genetics	RCV000157581	SCV000207327	uncertain significance	Cardiomyopathy	2014-10-28	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172735	SCV001740308	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172735	SCV001917224	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172735	SCV001928881	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172735	SCV001957241	likely benign	not provided		no assertion criteria provided	clinical testing