Submissions for variant NM_000089.4(COL1A2):c.1009G>A (p.Gly337Ser)

dbSNP: rs67865220

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002230964	SCV000627288	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-12-31	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 337 of the COL1A2 protein (p.Gly337Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta types I, III, and IV (PMID: 8829649, 21667357, 22206639, 24501682, 25944380, 26138843, 27510842, 27519266, 27748872, 28498836, 28810924). ClinVar contains an entry for this variant (Variation ID: 425643). 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.
Mendelics	RCV000987924	SCV001137418	pathogenic	Ehlers-Danlos syndrome, classic type	2019-05-28	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001250519	SCV001425314	pathogenic	Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta type III	2020-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001553203	SCV001774027	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Glycine substitution within the Gly-X-Y repeat in the collagenous domain of COL1A2; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10942108, 24501682, 32333414, 34367232, 22206639, 27510842, 26138843, 27748872, 16882741, 25944380, 8829649, 21667357, 28810924, 27519266, 28116328, 30715774, 17078022, 9016532, 28498836, 30886339, 32081708, 32166892, 24077912)
CeGaT Center for Human Genetics Tuebingen	RCV001553203	SCV002497533	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279258	SCV002564760	pathogenic	Osteogenesis imperfecta	2022-04-21	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV004535542	SCV004244672	pathogenic	COL1A2-related disorder	2023-11-01	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987562	SCV004803736	pathogenic	Ehlers-Danlos syndrome	2024-01-24	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.1009G>A (p.Gly337Ser) results in a non-conservative amino acid change in the Gly-X-Y repeat region of 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 250384 control chromosomes (gnomAD). c.1009G>A has been reported in the literature in individuals affected with Osteogenesis imperfecta (examples: Lindahl_2015, Andersson_2016, Ho Duy_2016). At-least one of these cases was reported as a de novo occurrence (Lindahl_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28498836, PMC4795106, 27519266). ClinVar contains an entry for this variant (Variation ID: 425643). Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989538	SCV004807330	uncertain significance	Ehlers-danlos syndrome, arthrochalasia type, 2	2024-03-26	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002279258	SCV004812414	pathogenic	Osteogenesis imperfecta	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in COL1A2 is predicted to replace glycine with serine at codon 337, p.(Gly337Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in glycine-altering in a Gly-X-Y collagen triple-helical repeat (PMID: 8218237). There is a small physicochemical difference between glycine and serine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in many unrelated individuals with a clinical diagnosis of osteogenesis imperfecta (PMID: 8829649, 33070251). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_VeryStrong, PM1, PM2_Supporting, PP3.
Department of Medical Sciences, Uppsala University	RCV000490720	SCV000574645	pathogenic	Osteogenesis imperfecta type I		no assertion criteria provided	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000993573	SCV001134943	pathogenic	Osteogenesis imperfecta type III	2020-01-06	no assertion criteria provided	clinical testing