ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.4913A>C (p.His1638Pro)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002295259 SCV002595091 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2022-07-15 criteria provided, single submitter clinical testing This variant is present in population databases (rs769518880, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. 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: "Deleterious"; PolyPhen-2: "Benign"; 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. This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1638 of the COL12A1 protein (p.His1638Pro).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004785568 SCV005399362 uncertain significance Bethlem myopathy 2 2019-08-28 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_004370.5(COL12A1):c.4913A>C in exon 27 of 66 of the COL12A1 gene. This substitution is predicted to create a moderate amino acid change from histidine to proline at position 1638 of the protein, NP_004361.3(COL12A1):p.(His1638Pro). The histidine at this position has low conservation (100 vertebrates, UCSC), and is located within the Fibronectin type III functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). It has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).

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