ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1403C>T (p.Thr468Met) (rs147957747)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183998 SCV000236492 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the VCL gene. The T468M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 9/24,024 (0.03%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The T468M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000533986 SCV000645839 uncertain significance Dilated cardiomyopathy 1W 2017-08-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 468 of the VCL protein (p.Thr468Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs147957747, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 202159). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on VCL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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