Submissions for variant NM_000089.4(COL1A2):c.1576G>A (p.Gly526Arg)

dbSNP: rs72658129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623717	SCV000741396	likely pathogenic	Inborn genetic diseases	2016-10-18	criteria provided, single submitter	clinical testing
Invitae	RCV002232602	SCV000818860	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 arginine, which is basic and polar, at codon 526 of the COL1A2 protein (p.Gly526Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of osteogenesis imperfecta (PMID: 10027910; Invitae). This variant is also known as Gly436Arg. ClinVar contains an entry for this variant (Variation ID: 521008). 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). This variant disrupts the p.Gly526 amino acid residue in COL1A2. Other variant(s) that disrupt this residue have been observed in individuals with COL1A2-related conditions (PMID: 11317364), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823152	SCV002073152	pathogenic	Osteogenesis imperfecta, perinatal lethal		criteria provided, single submitter	clinical testing	The missense variant p.G526R in COL1A2 (NM_000089.4) has been previously reported in multiple individuals with osteogenesis imperfecta-non lethal type (Bodian DL et al). The same variant was also detected in two siblings with juvenile osteoporosis who mainly had vertebral fractures. They had inherited this mutation from their asymptomatic father and a possible mosaicism had been hypothesized in their father (Dawson P A et al). The variant affects a glycine residue in the triple helix chain. Majority of the Glycine substitutions in the triple helix chain are disease causing. The variant has been classified in ClinVar as Likely Pathogenic/Pathogenic. The p.G526R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G526R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 526 of COL1A2 is conserved in all mammalian species. The nucleotide c.1576 in COL1A2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic
MGZ Medical Genetics Center	RCV002289909	SCV002579217	likely pathogenic	Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2	2022-04-29	criteria provided, single submitter	clinical testing
GeneDx	RCV003314628	SCV004014576	likely pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Reported using alternate nomenclature (p.G436R)) in the heterozygous state in two siblings with juvenile idiopathic osteoporosis and in their unaffected father (Dawson et al., 1999). The affected sibs presented with several compression fractures of the spine, short stature and/or mild SNHL.; Not observed in large population cohorts (gnomAD); 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 (Jovanovic et al., 2021); 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: 10027910)
CeGaT Center for Human Genetics Tuebingen	RCV003314628	SCV004162526	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	COL1A2: PM1:Strong, PM2, PM5, PS4:Moderate, PP3