ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.1924G>A (p.Gly642Arg) (rs794727472)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853367 SCV000996236 pathogenic COL2A1-related skeletal dysplasia 2019-01-24 criteria provided, single submitter clinical testing This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a different nucleotide change affecting the same amino acid residue (c.1925G>T p.Gly642Val) has been previously classified as pathogenic for COL2A1-related skeletal dysplasia by an external laboratory (https://www.ncbi.nlm.nih.gov/clinvar/variation/392715/). This variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In addition, there are reports of other pathogenic variants in this exon in the Human Gene Mutation Database (HGMD) (PMID:24949742), and in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/RCV000521936), to be associated with skeletal dysplasias. The Gly642Arg variant affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL2A1 gene, where the majority of pathogenic missense variants occur (PMID: 24077912). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1924G>A p.Gly642Arg variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002357 SCV001160264 likely pathogenic not specified 2019-02-04 criteria provided, single submitter clinical testing The COL2A1 c.1924G>A; p.Gly642Arg variant, to our knowledge, is not described in the medical literature or in gene-specific databases. It is also absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. 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). Based on available information, this variant is considered 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.

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