ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6199G>A (p.Glu2067Lys) (rs760446904)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000494333 SCV000337216 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000494333 SCV000581855 likely pathogenic not provided 2015-07-31 criteria provided, single submitter clinical testing The E2067K variant has been reported previously in an individual with Bethlem myopathy who was heterozygous for this change and did not have another identifiable pathogenic variant; however, additional clinical information was not provided and functional characterization of the variant was not completed (Foley et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E2067K 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 multiple missense variants in nearby residues (G2065D, G2074C/D, P2075L) have been reported in the Human Gene Mutation Database in association with COL6A3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, the variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000494333 SCV000892637 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Invitae RCV000817700 SCV000958278 uncertain significance Bethlem myopathy 1 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2067 of the COL6A3 protein (p.Glu2067Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs760446904, ExAC 0.001%). This variant has been observed in individuals affected with clinical features of Bethlem myopathy (PMID: 24271325, 26436962, Invitae) and in an individual affected with clinical features of limb girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 284554). 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 C15"). 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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