Submissions for variant NM_000089.4(COL1A2):c.964G>A (p.Gly322Ser)

dbSNP: rs72656394

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755946	SCV000883629	likely pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV002233745	SCV001205123	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-12-26	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 322 of the COL1A2 protein (p.Gly322Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 15241796, 24501682). ClinVar contains an entry for this variant (Variation ID: 618023). 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%. This variant disrupts the triple helix domain of COL1A2. 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 COL1A2, 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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001374625	SCV001571472	likely pathogenic	Osteogenesis imperfecta	2021-03-01	criteria provided, single submitter	research	The COL1A2 c.964G>A [p.Gly322Ser] missense variant alters a single amino acid in the encoded protein from glycine to serine. This variant has been previously reported in the heterozygous state in two individuals affected with osteogenesis imperfecta (PMID:24501682;15241796). The clinical presentation in one of these individuals appeared mild with less than 10 fractures in their lifetime and late onset hearing loss (PMID:15241796). This variant has also been reported in an apparently homozygous state in one individual with osteogenesis imperfecta and features of short stature, blue sclera, bowed limbs due to multiple fractures and dentinogenesis imperfecta (Pathologe 2015 36, 85-86). This variant is absent from the gnomAD human population database. This variant impacts a glycine residue in a Gly-X-Y repeat of the triple helix domain and computational tools indicate a deleterious impact to protein function. The available evidence indicates this is a likely pathogenic variant.
Johns Hopkins Genomics, Johns Hopkins University	RCV001543665	SCV001762351	likely pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form	2021-07-28	criteria provided, single submitter	clinical testing	COL1A2 c.964G>A has been identified in multiple individuals with osteogenesis imperfecta. This variant has a ClinVar entry and is absent from a large population dataset. p.Gly322Ser affects a glycine residue in the highly conserved Gly-X-Y repeat of the COL1A2 triple helix domain. Three bioinformatic tools queried predict that this substitution would be damaging and the glycine residue at this position is evolutionarily conserved across all species assessed. We consider COL1A2 c.964G>A be likely pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252228	SCV002523752	likely pathogenic	See cases	2020-07-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM1, PM2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001374625	SCV002571093	pathogenic	Osteogenesis imperfecta	2022-07-21	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.964G>A (p.Gly322Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251354 control chromosomes. c.964G>A has been reported in the literature in individuals affected with Osteogenesis Imperfecta. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.