ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.2894G>C (p.Arg965Pro) (rs201854898)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254951 SCV000322501 likely pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The R965P variant in the COL6A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R965P variant has been observed with a pathogenic variant on the opposite allele (in trans) in a patient referred for genetic testing at GeneDx with features suggestive of a COL6A2-related disorder. The R965P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R965P 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R965P as a likely pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254951 SCV000344670 uncertain significance not provided 2018-04-02 criteria provided, single submitter clinical testing
Invitae RCV000560338 SCV000657185 uncertain significance Bethlem myopathy 1 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 965 of the COL6A2 protein (p.Arg965Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 265525). 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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