ClinVar Miner

Submissions for variant NM_006731.2(FKTN):c.1046T>C (p.Val349Ala) (rs539089647)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519404 SCV000619897 uncertain significance not provided 2017-08-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FKTN gene. The V349A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). 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. Nevertheless, V349A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Invitae RCV000634053 SCV000755331 uncertain significance Walker-Warburg congenital muscular dystrophy 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 349 of the FKTN protein (p.Val349Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs539089647, ExAC 0.01%). This variant has not been reported in the literature in individuals with FKTN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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