ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.2998A>G (p.Lys1000Glu) (rs151244310)

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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 RCV000725669 SCV000338493 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000725669 SCV000620452 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing The K1000E variant in the COL6A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, it is reported as a variant of uncertain significance in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000338493.2; Landrum et al., 2015). This variant is observed in 5/9092 alleles (0.055%) from individuals of African background, and 6/61,502 alleles (0.010%) from individuals of non-Finnish European background, in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). The K1000E 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 addition, this substitution occurs at a position that is conserved across mammalian species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K1000E as a variant of uncertain significance.
Invitae RCV001055469 SCV001219863 uncertain significance Bethlem myopathy 1 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1000 of the COL6A2 protein (p.Lys1000Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs151244310, ExAC 0.05%). This variant has not been reported in the literature in individuals with COL6A2-related disease. ClinVar contains an entry for this variant (Variation ID: 285469). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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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