ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.707C>T (p.Thr236Ile) (rs886044270)

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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 RCV000658346 SCV000344210 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing
GeneDx RCV000658346 SCV000780118 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing The c.707 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). Multiple in-silico splice prediction models predict that c.707 C>T may damage or destroy the natural splice donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.707 C>T on splicing in this individual is unknown. If c.707 C>T does not alter splicing, it will result in the T236I missense change. The T236I 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function
Invitae RCV000804022 SCV000943912 uncertain significance Bethlem myopathy 1 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 236 of the COL6A3 protein (p.Thr236Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 289793). 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"). 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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