Submissions for variant NM_014000.3(VCL):c.2467C>T (p.Arg823Trp)

gnomAD frequency: 0.00006  dbSNP: rs779047174

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044351	SCV001208142	uncertain significance	Dilated cardiomyopathy 1W	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 823 of the VCL protein (p.Arg823Trp). This variant is present in population databases (rs779047174, gnomAD 0.003%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 202149). 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	RCV002453669	SCV002738243	uncertain significance	Cardiovascular phenotype	2024-07-21	criteria provided, single submitter	clinical testing	The c.2467C>T (p.R823W) alteration is located in exon 17 (coding exon 17) of the VCL gene. This alteration results from a C to T substitution at nucleotide position 2467, causing the arginine (R) at amino acid position 823 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001529152	SCV003820363	uncertain significance	not provided	2021-05-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486742	SCV004240244	uncertain significance	Cardiomyopathy	2022-07-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800321	SCV005422634	uncertain significance	not specified	2024-10-21	criteria provided, single submitter	clinical testing	Variant summary: VCL c.2467C>T (p.Arg823Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2467C>T has been reported in the literature in one individual affected with unknown cardiomyopathy (van Lint FHM_2019). These report(s) do 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. The following publication have been ascertained in the context of this evaluation (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 202149). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529152	SCV001742148	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529152	SCV001925660	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529152	SCV001931273	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529152	SCV001952868	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529152	SCV001968686	uncertain significance	not provided		no assertion criteria provided	clinical testing