ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.3809G>A (p.Arg1270Gln) (rs1057518127)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413666 SCV000491541 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The R1270Q variant in the COL6A3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1270Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1270Q 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1270Q as a variant of uncertain significance.
Invitae RCV000541654 SCV000657298 uncertain significance Bethlem myopathy 1 2017-06-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1270 of the COL6A3 protein (p.Arg1270Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a COL6A3-related disease. ClinVar contains an entry for this variant (Variation ID: 372995). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on COL6A3 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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