Submissions for variant NM_014000.3(VCL):c.1534C>T (p.Arg512Cys)

gnomAD frequency: 0.00004  dbSNP: rs781079975

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551156	SCV000645840	uncertain significance	Dilated cardiomyopathy 1W	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 512 of the VCL protein (p.Arg512Cys). This variant is present in population databases (rs781079975, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with VCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 468808). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000620528	SCV000736864	uncertain significance	Cardiovascular phenotype	2024-10-21	criteria provided, single submitter	clinical testing	The c.1534C>T (p.R512C) alteration is located in exon 11 (coding exon 11) of the VCL gene. This alteration results from a C to T substitution at nucleotide position 1534, causing the arginine (R) at amino acid position 512 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798891	SCV002043468	uncertain significance	Cardiomyopathy	2019-10-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017674	SCV004848215	likely benign	not specified	2018-06-02	criteria provided, single submitter	clinical testing	The p.Arg512Cys variant in VCL has not been previously reported in the literature, but has been reported as a variant of uncertain significance in ClinVar (Variation ID 468808). It has been identified in 0.02% (7/34278) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781079975). Computational prediction tools and conservation analysis suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The identification of this variant in an individual with HCM and an alternate cause of disease (LMM unpublished data) provides some support that it may not be disease causing. In summary, the aggregate of evidence suggests the p.Arg512Cys variant is likely benign. ACMG/AMP criteria applied: BS1_Supporting, BP4, BP5.