ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6868C>T (p.Arg2290Cys) (rs116608946)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000725025 SCV000196805 uncertain significance not provided 2017-04-14 criteria provided, single submitter clinical testing The R2290C variant has been reported previously in an individual with segmental dystonia who did not have another COL6A3 pathogenic variant or clinical features of a COL6A3-related disorder (Zech et al., 2015). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R2290C 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 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 association with COL6A3-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725025 SCV000333338 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000369192 SCV000428761 benign Collagen VI-related myopathy 2018-01-12 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.
Invitae RCV000817834 SCV000958417 uncertain significance Bethlem myopathy 1 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2290 of the COL6A3 protein (p.Arg2290Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs116608946, ExAC 0.02%). This variant has been observed in an individual affected with dystonia and in an individual with clinical suspicion of limb-girdle muscular dystrophy (PMID: 26004199, 30564623). ClinVar contains an entry for this variant (Variation ID: 162551). 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: "Not Available"; Align-GVGD: "Class C25"). 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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