ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.2362G>A (p.Gly788Ser)

dbSNP: rs67879854
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516519 SCV000612897 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV000707194 SCV000836280 pathogenic Osteogenesis imperfecta type I 2024-01-01 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 788 of the COL1A1 protein (p.Gly788Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 17078022, 27509835). ClinVar contains an entry for this variant (Variation ID: 447141). 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 COL1A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL1A1. 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 COL1A1, 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.
Fulgent Genetics, Fulgent Genetics RCV000763408 SCV000894137 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000516519 SCV002032567 pathogenic not provided 2021-12-08 criteria provided, single submitter clinical testing Occurs in the triple helical domain and replaces the glycine in the 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 (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic (ClinVar Variant ID# 447141; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 18412368, 27509835, 29595812, 32123938, 17078022)
3billion RCV000707194 SCV002572728 pathogenic Osteogenesis imperfecta type I 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 17078022, 27519266). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000447141). A different missense change at the same codon (p.Gly788Cys) has been reported to be associated with COL1A1-related disorder (PMID: 15241796). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences RCV004553128 SCV004121276 pathogenic COL1A1-related disorder 2023-10-30 criteria provided, single submitter clinical testing The COL1A1 c.2362G>A variant is predicted to result in the amino acid substitution p.Gly788Ser. The p.Gly788 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022). In addition, this variant was reported in multiple individuals with osteogenesis imperfecta (see examples: Table S1, Bardai et al. 2016. PubMed ID: 27509835; Table 1, Chandler et al. 2018. PubMed ID: 29595812; Table 1, Zhytnik et al. 2020. PubMed ID: 32166892; Table 1, Zhang et al. 2021. PubMed ID: 33942288). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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