Submissions for variant NM_000088.4(COL1A1):c.3226G>A (p.Gly1076Ser)

dbSNP: rs67394386

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596247	SCV000703178	pathogenic	not provided	2016-11-21	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000490696	SCV000992540	pathogenic	Osteogenesis imperfecta type III	2019-01-10	criteria provided, single submitter	research	ACMG codes: PS2, PS4, PM2, PP3, PP4, PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037391	SCV001200802	pathogenic	Osteogenesis imperfecta type I	2024-01-18	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 1076 of the COL1A1 protein (p.Gly1076Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 9101304, 26177859, 29150909, 29499418). In at least one individual the variant was observed to be de novo. This variant is also known as Gly898Ser. ClinVar contains an entry for this variant (Variation ID: 425618). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000596247	SCV001477574	likely pathogenic	not provided	2019-12-30	criteria provided, single submitter	clinical testing	The COL1A1 c.3226G>A; p.Gly1076Ser variant (rs67394386) is reported in the literature in multiple individuals who were affected with osteogenesis imperfect, and this variant was de novo in at least two of these individuals (Lindahl 2015, Lund 1997, Malmgren 2017, and Mrosk 2018). This variant is reported in ClinVar (Variation ID: 425618), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This codon is located in a triple helix repeat domain, and glycine substitutions are the most frequent pathogenic alterations in this region (Ben Amor 2011). The glycine at codon 1076 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic.
Baylor Genetics	RCV001330770	SCV001522562	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form	2019-12-24	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000596247	SCV002538781	pathogenic	not provided	2022-06-14	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 (HGMD); 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; This variant is associated with the following publications: (PMID: 27510842, 29499418, 31994750, 8218237, 32034735, 25944380, 21667357, 29150909, 19344236, 9016532, 17078022, 7695699, 25086671, 27519266, 9101304, 28116328, 29807018, 24863959, 33939306, 24077912, 27535533)
PreventionGenetics, part of Exact Sciences	RCV004551602	SCV004103007	pathogenic	COL1A1-related disorder	2023-09-20	criteria provided, single submitter	clinical testing	The COL1A1 c.3226G>A variant is predicted to result in the amino acid substitution p.Gly1076Ser. This variant (legacy nomenclature p.Gly898Ser) was reported in multiple individuals with osteogenesis imperfecta, being de novo when parental testing was performed (Lund. 1997. PubMed ID: 9101304; Table S2, Bowling. 2021. PubMed ID: 34930662; Higuchi. 2021. PubMed ID: 33939306; Table S2, Mei. 2022. PubMed ID: 35909573; Han. 2020. PubMed ID: 31994750). This variant is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Residues 179-1192, https://www.uniprot.org/; Legacy nomenclature in Marini. 2007. PubMed ID: 17078022 indicates amino acids 1-1012; Symoens. 2014. PubMed ID: 25146735). 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.
Department of Medical Sciences, Uppsala University	RCV000490696	SCV000574616	pathogenic	Osteogenesis imperfecta type III		no assertion criteria provided	clinical testing