Submissions for variant NM_000089.4(COL1A2):c.298G>A (p.Gly100Ser)

gnomAD frequency: 0.00001  dbSNP: rs1410254723

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002233933	SCV000752617	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2023-10-22	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 100 of the COL1A2 protein (p.Gly100Ser). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of autosomal dominant osteogenesis imperfecta and Ehlers-Danlos syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 526897). 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. 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.
Illumina Laboratory Services, Illumina	RCV004527693	SCV001786643	likely pathogenic	COL1A2-related disorder	2021-01-19	criteria provided, single submitter	clinical testing	The COL1A2 c.298G>A (p.Gly100Ser) variant is a missense variant. A literature search was conducted for the gene, cDNA change, and amino acid change. No publications were found based on this search, but there is an entry in ClinVar for this variant, in which the p.Gly100Ser variant is reported to have been observed in individuals with clinical features of osteogenesis imperfecta (ClinVar variation ID: 526897). The p.Gly100Ser variant is reported at a frequency of 0.000007 in the Total population of the Genome Aggregation Database, though this is based on two alleles in region of good sequence coverage so the variant is presumed rare. This variant affects a glycine residue within the Gly-Xaa-Yaa motifs of the highly conserved triple helix domain that play a critical role in protein structure and stability; this variant type is a known cause of disease (Robinson and Rauch 2019; Morlino et al. 2020). The Gly100Ser variant also falls within the cluster of glycine substitution variants clustering around the procollagen N-proteinase cleavage site that have been specifically linked to osteogenesis imperfecta/Ehlers-Danlos overlap syndrome (Morlino et al. 2020). Multiple in silico tools consistently predict a functional effect of this variant, but these predictions have not been assessed experimentally. Based on the collective evidence, the p.Gly100Ser variant is classified as likely pathogenic for COL1A2-related disorders.
GeneDx	RCV003238791	SCV003936447	likely pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing	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); 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34007986)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323646	SCV004029044	likely pathogenic	Ehlers-Danlos syndrome	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.298G>A (p.Gly100Ser) results in a non-conservative amino acid change located in the collagen triple helix repeat (IPR008160) of the encoded protein sequence and disrupts a Gly-X-Y repeat, a known mechanism of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251460 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.298G>A has been reported in the literature in at least one individual affected with Ehlers-Danlos Syndrome (e.g., Venable_2023). These data suggest the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 36896471). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GenomeConnect, ClinGen	RCV000845036	SCV000986872	not provided	Osteogenesis imperfecta type I		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 08/07/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.