ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.9344C>T (p.Pro3115Leu) (rs138109666)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522481 SCV000621857 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing The P3115L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P3115L variant is observed in 15/24,010 (0.06%) alleles from individuals of African background (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000533051 SCV000657452 uncertain significance Bethlem myopathy 1 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 3115 of the COL6A3 protein (p.Pro3115Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs138109666, ExAC 0.04%) but has not been reported in the literature in individuals with a COL6A3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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