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

dbSNP: rs72645357

Total submissions: 8

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	2025-02-14	criteria provided, single submitter	clinical testing	Also known as p.(G154R) using alternative nomenclature; 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 (PMID: 34007986); This variant is associated with the following publications: (PMID: 35855989, 36398383, 37270749, 11359465, 8799376, 16882741, 8669434, 25086671, 7695699, 8218237, 26177859, 12362986, 22589248, 17078022, 33942288, 2037280, 29669177, 34007986)
Labcorp Genetics (formerly Invitae), Labcorp	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, Medical Genetics	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