ClinVar Miner

Submissions for variant NM_000089.4(COL1A2):c.2701G>A (p.Gly901Ser)

gnomAD frequency: 0.00001  dbSNP: rs72659306
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001843974 SCV002103212 likely pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing PP3, PM1, PM2_supporting, PS4_moderate
GeneDx RCV001843974 SCV002512897 pathogenic not provided 2022-04-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces a glycine in a canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Jovanovic et al., 2021); This variant is associated with the following publications: (PMID: 17078022, 21239989, 31039433, 34007986, 9272740, 34025714, 18311573, 1634225)
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002276905 SCV002565572 likely pathogenic Ehlers-Danlos syndrome 2022-07-22 criteria provided, single submitter clinical testing
Invitae RCV002543291 SCV003516457 pathogenic Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 901 of the COL1A2 protein (p.Gly901Ser). This variant is present in population databases (rs72659306, gnomAD 0.0009%). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 9272740, 17078022). This variant is also known as G811S. ClinVar contains an entry for this variant (Variation ID: 1343353). 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 expected to disrupt COL1A2 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.

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