Submissions for variant NM_000089.4(COL1A2):c.1423G>A (p.Gly475Ser)

dbSNP: rs755058199

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001915322	SCV002175360	likely pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2024-04-12	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 475 of the COL1A2 protein (p.Gly475Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1398959). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230710	SCV003928684	likely pathogenic	Ehlers-Danlos syndrome	2023-04-12	criteria provided, single submitter	clinical testing	Variant summary: COL1A2 c.1423G>A (p.Gly475Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat region (IPR008160) of the encoded protein sequence and is predicted to disrupt the Gly-X-Y repeats. 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 250482 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1423G>A in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Other variants affecting Glycine residue in this region have been classified as pathogenic in ClinVar (examples: G475V, G472C, G472R). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003328686	SCV004035629	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located within the triple helical region and replaces the Gly position in the canonical Gly-X-Y repeat of COL1A2; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31039433)
Ambry Genetics	RCV004996080	SCV005561415	uncertain significance	Cardiovascular phenotype	2024-07-09	criteria provided, single submitter	clinical testing	The p.G475S variant (also known as c.1423G>A), located in coding exon 25 of the COL1A2 gene, results from a G to A substitution at nucleotide position 1423. The glycine at codon 475 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.