ClinVar Genomic variation as it relates to human health

The COL1A2 c.2314G>A; p.Gly772Ser variant (rs72658185), also known as p.Gly682Ser in alternative nomenclature, is reported in the literature in multiple individuals affected with osteogenesis imperfecta (Balasubramanian 2016, Marini 2007, Mrosk 2018, Nuytinck 2017). In at least one affected individual, the variant was absent from both parents, suggesting a de novo origin (Nuytinck 1997). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 772 is highly conserved, and this variant disrupts the repeating Gly-X-Y sequence motif of the collagen triple helix and is predicted to impair collagen function (Ben Amor 2011). Based on available information, this variant is considered to be pathogenic. References: Balasubramanian M et al. Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta. Am J Med Genet A. 2016 Feb;170A(2):476-481. Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Marini JC et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007 Mar;28(3):209-21. Mrosk J et al. Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone. 2018 May;110:368-377. Nuytinck L et al. Osteogenesis imperfecta phenotypes resulting from serine for glycine substitutions in the alpha2(I) collagen chain. Eur J Hum Genet. 1997 May-Jun;5(3):161-7.

ACMG classification criteria: PS4 moderate, PM2 moderate, PP1 strong, PP3 supporting

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000420022 / PMID: 9272740). Different missense change at the same codon (p.Gly772Arg, p.Gly772Cys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001468991, VCV001701996). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9272740, 29499418, 17078022, 23934635, 26471105, 30886339, 31429852, 32123938, 33939306, 35822426, 32166892, 35154279)

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 772 of the COL1A2 protein (p.Gly772Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 9272740, 17078022, 23934635, 26471105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420022). 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 COL1A2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Heterozygous missense variants causing severe and lethal forms of osteogenesis imperfecta (MIM#166210, #259420, #166220) are due to a dominant negative mechanism, whereas biallelic loss of function variants result in the autosomal recessive form of Ehlers-Danlos syndrome (MIM#225320). The exact mechanism of disease for the autosomal dominant form of Ehlers-Danlos syndrome (MIM#2617821) remains unclear, however variants have been shown to result in whole or partial skipping of exon 6 (PMID: 12362985, 31218159). (I) 0108 - This gene is associated with both recessive and dominant disease. Most phenotypes associated with this gene are autosomal dominant, however the cardiac valvular type of Ehlers-Danlos syndrome (MIM#225320) is recessively inherited (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301472). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the annotated collagen triple helix and affects the Gly of a Gly-X-Y repeat (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with osteogenesis imperfecta (PMID: 23934635, 31429852, 31447884, 33939306). It has also been reported multiple times as pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign