Submissions for variant NM_014000.3(VCL):c.1671C>T (p.Asp557=)

gnomAD frequency: 0.00228  dbSNP: rs137877092

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038803	SCV000062481	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing	p.Asp557Asp in exon 12 of VCL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and has been identifie d in 1.6% (105/6612) of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs137877092).
GeneDx	RCV000038803	SCV000236470	benign	not specified	2014-07-02	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.
Ambry Genetics	RCV000246206	SCV000318689	benign	Cardiovascular phenotype	2015-07-15	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.
Illumina Laboratory Services, Illumina	RCV001086811	SCV000364931	likely benign	Dilated cardiomyopathy 1W	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV001086811	SCV000559716	benign	Dilated cardiomyopathy 1W	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528236	SCV000884868	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769112	SCV000900485	benign	Cardiomyopathy	2016-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038803	SCV001363187	benign	not specified	2019-03-04	criteria provided, single submitter	clinical testing	Variant summary: The variant, VCL c.1671C>T 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 0.0049 in 277182 control chromosomes in the gnomAD database. The highest allele frequencies were detected within the South Asian (0.018) and the Finnish subpopulation (0.016), including 12 and 7 homozygotes, respectively. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 720 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. The variant, c.1671C>T has been reported in the literature in individuals affected with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (Pugh 2014, Bottillo 2016), however, without evidence for pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (four classifying it as benign and one as a VUS). Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528236	SCV001739626	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038803	SCV001917165	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528236	SCV001956190	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528236	SCV001974324	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038803	SCV002034293	benign	not specified		no assertion criteria provided	clinical testing