ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000487673 SCV000202552 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487673 SCV000575300 uncertain significance not provided 2017-12-01 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 2019-12-23 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 been observed in individuals affected with limb-girdle muscular dystrophy (PMID: 30564623). 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.
Athena Diagnostics Inc RCV000487673 SCV001143275 uncertain significance not provided 2019-06-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001141518 SCV001301869 benign Collagen VI-related myopathy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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