ClinVar Genomic variation as it relates to human health

The COL1A1 c.3118G>A; p.Gly1040Ser variant (rs72653178), also known as p.Gly862Ser, is reported in the literature in several individuals affected with osteogenesis imperfecta (Bardai 2016, Lindahl 2015, Maioli 2019, Mrosk 2018, Obafemi 2008). This variant is reported in ClinVar (Variation ID: 17330), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 1040 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This codon is located in a triple helix repeat domain, and glycine substitutions are the most frequent pathogenic alterations in this region (Ben Amor 2011). Based on available information, this variant is considered to be pathogenic. References: Bardai G et al. DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int. 2016 Dec;27(12):3607-3613. Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Lindahl K et al. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. Eur J Hum Genet. 2015 Aug;23(8):1112. Maioli M et al. Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients. Eur J Hum Genet. 2019 Jul;27(7):1090-1100. Mrosk J et al. Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone. 2018 May;110:368-377. Obafemi AA et al. Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet A. 2008 Nov 1;146A(21):2725-32.

Based on the classification scheme VCGS_Germline_v1.3.3, 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 and are associated with osteogenesis imperfecta. Haploinsufficiency and missense variants that disrupt collagen structure are both known to be pathogenic (PMID: 12362985). (I) 0107 - This gene is associated with autosomal dominant disease. (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 well-established functional Gly-X-Y motif. Variants that disrupt the glycine of the Gly-X-Y motif are known to product structural defects in the collagen molecule (PMID: 12362985). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in many individuals with osteogenesis imperfecta in ClinVar and the literature (PMID: 17078022, 26177859, 27509835). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1040 of the COL1A1 protein (p.Gly1040Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta type III and osteogenesis imperfecta type III or IV (PMID: 7789952, 18670065, 18798308, 26177859, 27509835). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17330). 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 COL1A1 protein function. Experimental studies have shown that this missense change affects COL1A1 function (PMID: 7695699, 8218237, 9016532, 17078022, 18670065, 19344236). This variant disrupts the triple helix domain of COL1A1. 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 COL1A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.

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: 0.98; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017330). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25944380). 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 in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9101304, 32234057, 8125479, 27509835, 26177859, 29499418, 18670065, 18798308, 7789952, 30886339, 31715670, 31994750, 32436246, 32123938, 33939306)