ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.3774C>G (p.Asp1258Glu)

dbSNP: rs375043994
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001556906 SCV001778571 uncertain significance not provided 2020-10-21 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV002032621 SCV002217040 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2023-10-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1258 of the COL12A1 protein (p.Asp1258Glu). This variant is present in population databases (rs375043994, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1194241). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL12A1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV003264060 SCV003980444 uncertain significance Inborn genetic diseases 2023-04-05 criteria provided, single submitter clinical testing The c.3774C>G (p.D1258E) alteration is located in exon 19 (coding exon 18) of the COL12A1 gene. This alteration results from a C to G substitution at nucleotide position 3774, causing the aspartic acid (D) at amino acid position 1258 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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