Submissions for variant NM_014000.3(VCL):c.1928C>T (p.Thr643Met)

gnomAD frequency: 0.00004  dbSNP: rs150643310

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756899	SCV000884871	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The p.Thr643Met variant (rs150643310) has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.004% (identified in 12 out of 277,074 chromosomes). The threonine at codon 643 is highly conserved considering 13 species up to C. elegans (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on VCL protein structure/function (SIFT: damaging, PolyPhen2: damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Thr643Met variant cannot be determined with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818461	SCV000959076	uncertain significance	Dilated cardiomyopathy 1W	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 643 of the VCL protein (p.Thr643Met). This variant is present in population databases (rs150643310, gnomAD 0.008%). 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: 487627). 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: "Probably Damaging"; 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.
Ambry Genetics	RCV002413656	SCV002717475	uncertain significance	Cardiovascular phenotype	2023-07-15	criteria provided, single submitter	clinical testing	The p.T643M variant (also known as c.1928C>T), located in coding exon 14 of the VCL gene, results from a C to T substitution at nucleotide position 1928. The threonine at codon 643 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506387	SCV002812178	uncertain significance	Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15	2021-07-23	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656206	SCV000678400	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome