ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6156G>C (p.Lys2052Asn) (rs398124125)

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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 RCV000723513 SCV000112866 uncertain significance not provided 2013-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000723513 SCV000621515 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL6A3 gene. The c.6156 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.6156 G>C variant is not observed in large population cohorts (Lek et al., 2016). Several in-silico splice prediction models predict that c.6156 G>C weakens or destroys the natural donor site for intron 15 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.6156 G>C variant does not affect splicing, it will result in the K2052N missense change. The K2052N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001055334 SCV001219721 uncertain significance Bethlem myopathy 1 2019-01-25 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 2052 of the COL6A3 protein (p.Lys2052Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 15 of the COL6A3 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 94954). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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