ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.5224C>T (p.Arg1742Cys) (rs530680231)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489488 SCV000576538 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing The c.5224 C>T variant in the COL12A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.5224 C>T variant is observed in 15/16,412 (0.1%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). In-silico splice prediction models predict that c.5224 C>T may create or enhance a cryptic splice donor site in exon 29, which may supplant the natural donor site. However, in the absence of RNA/functional studies, the actual effect of the c.5224 C>T change in this individual is unknown. If c.5224 C>T does not alter splicing, it will result in the R1742C missense change. The R1742C 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. 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. We interpret c.5224 C>T as a variant of uncertain significance.
Invitae RCV000803721 SCV000943604 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1742 of the COL12A1 protein (p.Arg1742Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs530680231, ExAC 0.09%). This variant has not been reported in the literature in individuals with COL12A1-related disease. ClinVar contains an entry for this variant (Variation ID: 426164). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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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