ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6470C>T (p.Pro2157Leu) (rs372281922)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482756 SCV000573231 uncertain significance not provided 2017-02-21 criteria provided, single submitter clinical testing The c.6470 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.6470 C>T 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). Multiple in-silico splice prediction models predict c.6470 C>T may damage the natural splice donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.6470 C>T does not alter splicing, it will result in the P2157L missense change. The P2157L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with COL6A3-related disorders (Stenson et al., 2014).
Invitae RCV001236183 SCV001408896 uncertain significance Bethlem myopathy 1 2019-09-17 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2157 of the COL6A3 protein (p.Pro2157Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs372281922, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 423522). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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