ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.2623G>A (p.Ala875Thr) (rs199606147)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726187 SCV000342724 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing
GeneDx RCV000726187 SCV000581727 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL6A2 gene. The A875T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A875T variant is observed in 6/3630 (0.2%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A875T 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. Additionally, missense variants in nearby residues (D871N, R876S/H) have been reported in the Human Gene Mutation Database in association with COL6A2-related disorders (Stenson et al., 2014). However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000694478 SCV000822926 uncertain significance Bethlem myopathy 1 2019-05-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 875 of the COL6A2 protein (p.Ala875Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs199606147, ExAC 0.2%). This variant has not been reported in the literature in individuals with COL6A2-related disease. ClinVar contains an entry for this variant (Variation ID: 288567). 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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