ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.2314C>T (p.Pro772Ser) (rs370256196)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686039 SCV000813542 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2018-03-12 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 772 of the COL12A1 protein (p.Pro772Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs370256196, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL12A1-related disease. 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV001193906 SCV001363074 uncertain significance not specified 2019-08-01 criteria provided, single submitter clinical testing Variant summary: COL12A1 c.2314C>T (p.Pro772Ser) results in a non-conservative amino acid change located in a fibronectin type III repeat (IPR003961) in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 280790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2314C>T in individuals affected with Bethlem myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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