ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2000C>T (p.Thr667Met) (rs794729187)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183978 SCV000236472 uncertain significance not provided 2012-11-12 criteria provided, single submitter clinical testing p.Thr667Met (ACG>ATG): c.2000 C>T in exon 14 of the VCL gene (NM_014000.2). The Thr667Met variant in the VCL gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr667Met results in a non-conservative amino acid substitution of a neutral, polar Threonine with a non-polar Methionine at a position that is class conserved across species. In silico analysis predicts Thr667Met is possibly damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Thr667Met was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy. Hereditary dilated cardiomyopathy (DCM) is primarily an autosomal dominant disease characterized by left ventricular enlargement and systolic dysfunction in the absence of other cardiac, systemic or environmental causes (Hershberger R et al., 2009). Although rare, mutations in the VCL gene have been reported in association with DCM (Maeda M et al., 1997; Olson T et al., 2002). With the clinical and molecular information available at this time, we cannot definitively determine if Thr667Met is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV000546287 SCV000645851 uncertain significance Dilated cardiomyopathy 1W 2017-03-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 667 of the VCL protein (p.Thr667Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 202146). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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