ClinVar Genomic variation as it relates to human health

The c.1801G>A;p.(Gly601Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 425649; PMID: 25944380; PMID: 21667357; PMID: 16705691; PMID: 11317364) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (COLFI - triple helix domain; PMID: 19344236; PMID: 17078022) - PM1. This variant is not present in population databases (rs72658143- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 25944380) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A2. 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 COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). ClinVar contains an entry for this variant (Variation ID: 425649). This variant is also known as Gly511Ser. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 11317364, 26177859). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 601 of the COL1A2 protein (p.Gly601Ser).

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; Occurs in the triple helical domain and replaces a glycine in a 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 (Jovanovic et al., 2021); This variant is associated with the following publications: (PMID: 25086671, 16705691, 35154279, 11317364, 26177859, 27510842, 25944380, 21667357, 17078022, 31994750, 33470886, 34122524, 34341165, 35909573, 34902613, 34007986)

ACMG classification criteria: PS4 strong, PM1 moderated, PM2 moderated, PP3 supporting, PP4

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: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000425649). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11317364, 16705691, 21667357, 25944380). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 25944380). A different missense change at the same codon (p.Gly601Asp) has been reported to be associated with COL1A2 related disorder (PMID: 17078022). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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, type IV (MIM #166220). (I) 0108 - This gene is associated with both recessive and dominant disease. Osteogenesis imperfecta is dominantly inherited, however Ehlers-Danlos syndrome can be either dominant or recessive (OMIM). (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 collagen triple helix motif. The variant affects the glycine of a Gly-X-Y repeat (NCBI, PDB). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternate changes at the same residue, to aspartic acid and valine, have previously been reported as pathogenic (LOVD, PMID: 17078022). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in more than ten patients with osteogenesis imperfecta (ClinVar, HGMD, PMIDs: 11317364, 17078022, 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