ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.5893C>T (p.Arg1965Cys) (rs200487396)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441199 SCV000518363 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing The R1965C variant in the COL12A1 gene has been reported previously in 3 affected individuals from a single family presenting with a Bethlem myopathy like phenotype (Hicks et al, 2014). The R1965C variant was not observed at any significant frequency in approximately 6,200 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 R1965C 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. Functional studies performed by Hicks et al. (2014), showed less abundant and disorganized collagen XII with significant intracellular retention, and showed the up-regulation of the genes involved in the unfolded protein response (UPR) pathway, and dilation and swelling of the endoplasmic reticulum (ER), suggesting that the R1965C variant is causing ER stress. However, these studies were perform within the patient's cells. Therefore, we interpret R1965C as a variant of uncertain significance.
Invitae RCV000702038 SCV000830866 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1965 of the COL12A1 protein (p.Arg1965Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200487396, ExAC 0.03%). This variant has been reported to segregate with Bethlem myopathy in a single family (PMID: 24334769). ClinVar contains an entry for this variant (Variation ID: 204297). Experimental studies have shown that this missense change disrupts COL12A1 protein localization (PMID: 24334769). 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.
OMIM RCV000186501 SCV000239881 pathogenic Bethlem myopathy 2 2014-05-01 no assertion criteria provided literature only

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