Submissions for variant NM_001844.5(COL2A1):c.2910_2918del (p.Pro971_Pro973del)

dbSNP: rs2136526614

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379358	SCV001577145	likely pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with COL2A1-related conditions. This variant is not present in population databases (ExAC no frequency). This variant, c.2910_2918del, results in the deletion of 3 amino acid(s) of the COL2A1 protein (p.Pro971_Pro973del), but otherwise preserves the integrity of the reading frame. 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). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388006	SCV004099703	likely pathogenic	Achondrogenesis type II	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: COL2A1 c.2910_2918delACCAGGTCC (p.Pro971_Pro973del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein including one Glycine in a Gly-X-Y repeat region. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. The variant was absent in 250708 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2910_2918delACCAGGTCC in individuals affected with Achondrogenesis, Type II and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.