Submissions for variant NM_014000.3(VCL):c.1346G>A (p.Arg449Gln)

dbSNP: rs755234443

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481865	SCV000573039	uncertain significance	not provided	2017-02-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the VCL gene. The R449Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R449Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the R449Q variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064521	SCV001229429	uncertain significance	Dilated cardiomyopathy 1W	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 449 of the VCL protein (p.Arg449Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 423351). 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	RCV004678723	SCV005179532	uncertain significance	Cardiovascular phenotype	2024-05-30	criteria provided, single submitter	clinical testing	The p.R449Q variant (also known as c.1346G>A), located in coding exon 10 of the VCL gene, results from a G to A substitution at nucleotide position 1346. The arginine at codon 449 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.