Submissions for variant NM_000089.4(COL1A2):c.2314G>A (p.Gly772Ser)

dbSNP: rs72658185

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481739	SCV000568353	pathogenic	not provided	2023-10-20	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: 9272740, 29499418, 17078022, 23934635, 26471105, 30886339, 31429852, 32123938, 33939306, 35822426, 32166892, 35154279)
Invitae	RCV002230922	SCV000627313	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-10-27	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 772 of the COL1A2 protein (p.Gly772Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 9272740, 17078022, 23934635, 26471105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420022). 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%. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000481739	SCV001472350	pathogenic	not provided	2019-11-08	criteria provided, single submitter	clinical testing	The COL1A2 c.2314G>A; p.Gly772Ser variant (rs72658185), also known as p.Gly682Ser in alternative nomenclature, is reported in the literature in multiple individuals affected with osteogenesis imperfecta (Balasubramanian 2016, Marini 2007, Mrosk 2018, Nuytinck 2017). In at least one affected individual, the variant was absent from both parents, suggesting a de novo origin (Nuytinck 1997). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 772 is highly conserved, and this variant disrupts the repeating Gly-X-Y sequence motif of the collagen triple helix and is predicted to impair collagen function (Ben Amor 2011). Based on available information, this variant is considered to be pathogenic. References: Balasubramanian M et al. Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta. Am J Med Genet A. 2016 Feb;170A(2):476-481. Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Marini JC et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007 Mar;28(3):209-21. Mrosk J et al. Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone. 2018 May;110:368-377. Nuytinck L et al. Osteogenesis imperfecta phenotypes resulting from serine for glycine substitutions in the alpha2(I) collagen chain. Eur J Hum Genet. 1997 May-Jun;5(3):161-7.
Revvity Omics, Revvity	RCV000481739	SCV002017446	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002244949	SCV002512452	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form	2021-05-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderate, PM2 moderate, PP1 strong, PP3 supporting
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279242	SCV002564784	likely pathogenic	Osteogenesis imperfecta	2021-11-30	criteria provided, single submitter	clinical testing
3billion	RCV002244949	SCV004013619	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000420022 / PMID: 9272740). Different missense change at the same codon (p.Gly772Arg, p.Gly772Cys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001468991, VCV001701996). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003988847	SCV004805257	likely pathogenic	Ehlers-danlos syndrome, arthrochalasia type, 2	2024-03-25	criteria provided, single submitter	research