ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1940C>T (p.Ala647Val) (rs534449109)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523002 SCV000621090 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing The c.1940 C>T (A647V) variant of uncertain significance in the VCL gene has been reported in a one year-old Spanish male diagnosed with HCM (Mademont-Soler et al., 2017). It has also been observed in one other individual referred for DCM genetic testing at GeneDx, however, this individual also harbored a pathogenic variant in a different gene. Thus far, no segregation data are available for the published case or the case observed at GeneDx. This variant is also observed in 7/111518 (0.006%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This variant is located in exon 14 of the VCL gene and may be functionally significant at the mRNA or protein level. At the mRNA level, c.1940 C>T is located at a nucleotide that is conserved across species and in silico splice prediction algorithms predict that it creates a cryptic splice donor site which may lead to abnormal gene splicing. However, at the protein level, A647V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, in the absence of functional expression studies, the physiological consequence of this variant cannot be precisely determined.

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