ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.1331G>T (p.Gly444Val)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287131 SCV001473780 likely pathogenic none 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 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. This variant is not present in population databases (ExAC no frequency). 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. 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). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001384787 SCV001832389 likely pathogenic not provided 2019-11-30 criteria provided, single submitter clinical testing

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