Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812387 | SCV001471672 | uncertain significance | not provided | 2019-08-26 | criteria provided, single submitter | clinical testing | The COL2A1 c.1052G>T; p.(Gly351Val) variant was reported in a single patient with congenital spondylo-epiphyseal dysplasia without evidence of segregation with disease (Terhal 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at position 351 is highly conserved in the triple helix repeat and computational analyses of the effects of the p.(Gly351Val) variant on protein structure and function is deleterious (SIFT: damaging, PolyPhen-2: probably damaging). Without functional studies however, there is not enough evidence to classify the p.(Gly351Val) variant with certainty. |
| Labcorp Genetics |
RCV001812387 | SCV002131853 | pathogenic | not provided | 2023-09-27 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with clinical features of spondyloepiphyseal dysplasia congenita (PMID: 25604898; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 351 of the COL2A1 protein (p.Gly351Val). ClinVar contains an entry for this variant (Variation ID: 993615). For these reasons, this variant has been classified as Pathogenic. 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). 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. |
| Kasturba Medical College, |
RCV003389070 | SCV004100882 | likely pathogenic | Spondyloepiphyseal dysplasia congenita | criteria provided, single submitter | clinical testing |