ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.2746G>A (p.Val916Ile) (rs563043611)

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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 RCV000734240 SCV000862364 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing
GeneDx RCV000734240 SCV000569926 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL6A1 gene. The V916I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. 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 V916I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. 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 RCV000537709 SCV000657046 uncertain significance Bethlem myopathy 1 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 916 of the COL6A1 protein (p.Val916Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs563043611, ExAC 0.04%) but has not been reported in the literature in individuals with a COL6A1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The isoleucine 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 with uncertain impact on protein function. There is no indication that it causes disease, but 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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