Submissions for variant NM_014000.3(VCL):c.829C>A (p.Leu277Met)

gnomAD frequency: 0.00010  dbSNP: rs71579353

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617420	SCV000736662	uncertain significance	Cardiovascular phenotype	2024-05-30	criteria provided, single submitter	clinical testing	The p.L277M variant (also known as c.829C>A), located in coding exon 7 of the VCL gene, results from a C to A substitution at nucleotide position 829. The leucine at codon 277 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) and sudden cardiac death (Vasile VC et al. Biochem. Biophys. Res. Commun., 2006 Jul;345:998-1003; Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). However, this variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000645321	SCV000767064	uncertain significance	Dilated cardiomyopathy 1W	2022-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 277 of the VCL protein (p.Leu277Met). This variant is present in population databases (rs71579353, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 16712796, 24503780, 27930701, 31513939). ClinVar contains an entry for this variant (Variation ID: 12198). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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.
Center for Human Genetics, University of Leuven	RCV000768535	SCV000886854	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845477	SCV000987572	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
GeneDx	RCV000994445	SCV002032741	uncertain significance	not provided	2022-05-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24503780, 25179549, 28218286, 24062880, 17097056, 27957775, 27930701, 31513939, 29875424, 16712796)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298443	SCV002598876	likely benign	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: VCL c.829C>A (p.Leu277Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251860 control chromosomes. The observed variant frequency is approximately 4.3 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.829C>A has been reported in the literature in at-least one individual with hypertrophic cardiomyopathy (HCM) and continues to be reported as a VUS in settings of multigene panel testing among cohorts of affected individuals with dilated cardiomyopathy (DCM), sudden cardiac death (SCD) and HCM (example, Vasile_2006, Pugh_2014, Sanchez_2016, Mazzarotto_2019, Robyns_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV002496333	SCV002781778	uncertain significance	Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15	2021-07-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149568	SCV003837786	uncertain significance	Cardiomyopathy	2021-09-23	criteria provided, single submitter	clinical testing
OMIM	RCV000012982	SCV000033227	pathogenic	Hypertrophic cardiomyopathy 15	2006-07-07	no assertion criteria provided	literature only