Submissions for variant NM_014000.3(VCL):c.1557C>A (p.Ile519=)

gnomAD frequency: 0.00466  dbSNP: rs150120464

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038799	SCV000062477	benign	not specified	2012-04-17	criteria provided, single submitter	clinical testing	Ile519Ile in Exon 12 of VCL: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence and has been identified in 1.3% (49/3738) of Africa n American chromosomes from a broad population by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS; dbSNP rs150120464).
GeneDx	RCV000038799	SCV000169798	benign	not specified	2013-03-11	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	RCV000230596	SCV000289908	benign	Dilated cardiomyopathy 1W	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241646	SCV000318717	benign	Cardiovascular phenotype	2015-10-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769110	SCV000900483	benign	Cardiomyopathy	2016-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038799	SCV000920336	benign	not specified	2018-03-06	criteria provided, single submitter	clinical testing	Variant summary: VCL c.1557C>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 277816 control chromosomes in the gnomAD database and literature, including 4 homozygotes. The observed variant frequency is approximately 87.11 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 benign. c.1557C>A has been reported in the literature in one individual affected with palpitations (Campuzano_2012). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811275	SCV001471679	benign	not provided	2019-11-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504901	SCV002805244	benign	Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15	2021-09-20	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038799	SCV001924510	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038799	SCV001951179	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000038799	SCV001972972	benign	not specified		no assertion criteria provided	clinical testing