ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.4510C>T (p.Arg1504Trp) (rs144223596)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487673 SCV000575300 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487673 SCV000202552 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000487673 SCV000618187 uncertain significance not provided 2018-07-27 criteria provided, single submitter clinical testing The R1504W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1504W variant is observed in 36/66,690 (0.05%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. This substitution occurs at a position that is conserved in mammals, 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 RCV000528795 SCV000657317 uncertain significance Bethlem myopathy 1 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1504 of the COL6A3 protein (p.Arg1504Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs144223596, ExAC 0.05%). This variant has not been reported in the literature in individuals with COL6A3-related disease. ClinVar contains an entry for this variant (Variation ID: 166943). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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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