Submissions for variant NM_001844.5(COL2A1):c.1636G>A (p.Gly546Ser)

dbSNP: rs886044555

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000489443	SCV000345403	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000489443	SCV000576764	pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing	Reported as heterozygous in five individuals with spondyloepiphyseal dysplasia congenita from one family (Xu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as G346S; Located in the anti-codon loop and is a part of the anti-codon triplet that pairs with its respective mRNA codon. A Occurs in the triple helical domain and replaces the glycine in the 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 (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28738883, 24013370, 27059630, 24736929)
Ambry Genetics	RCV000622408	SCV000742812	likely pathogenic	Inborn genetic diseases	2017-08-10	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000489443	SCV001832339	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Invitae	RCV000489443	SCV002236790	pathogenic	not provided	2024-01-07	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 546 of the COL2A1 protein (p.Gly546Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spondyloepiphyseal dysplasia congenita and spondyloepimetaphyseal dysplasia, Strudwick type (PMID: 24736929, 28738883). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 290774). 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 COL2A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL2A1. 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 COL2A1, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987496	SCV004803695	pathogenic	Achondrogenesis type II	2024-01-23	criteria provided, single submitter	clinical testing	Variant summary: COL2A1 c.1636G>A (p.Gly546Ser) 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 249234 control chromosomes (gnomAD). c.1636G>A has been reported in the literature in multiple individuals affected with skeletal dysplasia and spondyloepiphyseal dysplasia congenita with evidence of cosegregation with disease (Xu_2014, Chen_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24736929, 28738883). ClinVar contains an entry for this variant (Variation ID: 290774). Based on the evidence outlined above, the variant was classified as pathogenic.