ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.8819C>T (p.Thr2940Met) (rs200626456)

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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 RCV000178441 SCV000230520 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000286598 SCV000428708 likely benign Collagen VI-related myopathy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV000557223 SCV000657440 uncertain significance Bethlem myopathy 1 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 2940 of the COL6A3 protein (p.Thr2940Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs200626456, ExAC 0.06%) but has not been reported in the literature in individuals with a COL6A3-related disease. ClinVar contains an entry for this variant (Variation ID: 197416). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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