ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.4691T>C (p.Leu1564Ser) (rs1554181762)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523311 SCV000620532 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing The L1564S variant in the COL12A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L1564S 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 not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, we interpret L1564S as a variant of uncertain significance.
Invitae RCV000811756 SCV000952039 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 1564 of the COL12A1 protein (p.Leu1564Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451784). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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