Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001384787 | SCV001473780 | likely pathogenic | not provided | 2019-12-11 | criteria provided, single submitter | clinical testing | The COL2A1 c.1331G>T; p.Gly444Val variant, to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 444 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant disrupts the repeating Gly-X-Y sequence motif of the collagen triple helix and is predicted to impair collagen function (Barat-Houari 2016). Indeed, another variant at this residue (p.Gly444Asp) has been reported in an individual affected with spondylo-epiphyseal dysplasia congenital (Terhal 2012). Based on available information, the p.Gly444Val variant is considered to be likely pathogenic. References: Barat-Houari M et al. Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies. Hum Mutat. 2016 Jan;37(1):7-15. Terhal PA et al. Mutation-based growth charts for SEDC and other COL2A1 related dysplasias. Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C(3):205-16. |
| Invitae | RCV001384787 | SCV001584434 | pathogenic | not provided | 2020-02-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of COL2A1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 444 of the COL2A1 protein (p.Gly444Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 10612821, 26443184) compared to the general population (ExAC). |
| Blueprint Genetics | RCV001384787 | SCV001832389 | likely pathogenic | not provided | 2019-11-30 | criteria provided, single submitter | clinical testing |