ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.994G>A (p.Gly332Arg)

dbSNP: rs72645357
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029586 SCV000052238 pathogenic Osteogenesis imperfecta 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000480634 SCV000567265 pathogenic not provided 2023-04-28 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; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G154R) using alternative nomenclature; This variant is associated with the following publications: (PMID: 11359465, 8799376, 16882741, 8669434, 25086671, 7695699, 8218237, 26177859, 12362986, 22589248, 17078022, 2037280, 33942288)
Invitae RCV000692051 SCV000819858 pathogenic Osteogenesis imperfecta type I 2023-05-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 17312). This variant is also known as Gly154Arg. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 2037280, 8669434, 17078022, 22589248, 25086671, 26177859). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 332 of the COL1A1 protein (p.Gly332Arg).
Fulgent Genetics, Fulgent Genetics RCV000763413 SCV000894142 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
3billion RCV000490676 SCV002572545 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form 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: 19344236). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017312). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 17078022, 2037280, 22589248, 8669434). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences RCV004549377 SCV004103668 pathogenic COL1A1-related disorder 2023-08-14 criteria provided, single submitter clinical testing The COL1A1 c.994G>A variant is predicted to result in the amino acid substitution p.Gly332Arg. The p.Gly332Arg variant was reported in multiple individuals with osteogenesis imperfecta (see examples: reported as p.Gly154Arg in Fig. 4C, Pruchno et al 1991. PubMed ID: 2037280; reported as de novo in Table S1, Lindahl et al 2015. PubMed ID: 26177859; reported as de novo in Table 1, Zhang et al 2021. PubMed ID: 33942288). The p.Gly332Arg 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). 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.
OMIM RCV000018853 SCV000039136 pathogenic Osteogenesis imperfecta type III 1996-01-11 no assertion criteria provided literature only
Department of Medical Sciences, Uppsala University RCV000490676 SCV000574644 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form no assertion criteria provided clinical testing

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