ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.1094G>T (p.Gly365Val)

dbSNP: rs66494876
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001812395 SCV001471707 pathogenic not provided 2020-01-28 criteria provided, single submitter clinical testing The COL1A1 c.1094G>T; p.Gly365Val variant (rs66494876) is reported in the literature in at least one individual affected with osteogenesis imperfecta (Marini 2007). 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 365 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). Additionally, other variants at this codon (c.1093G>A, p.Gly365Ser; c.1094G>C, p.Gly365Ala) have been reported in individuals with osteogenesis imperfecta (Li 2019, Marini 2007). Based on available information, this variant is considered to be pathogenic. References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Li L et al. Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta. Hum Mutat. 2019 May;40(5):588-600. 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.
Institute of Human Genetics, University Hospital Muenster RCV002222200 SCV002499684 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Osteogenesis imperfecta type I 2022-03-24 criteria provided, single submitter clinical testing ACMG categories: PS2,PM1,PM2,PP3,PP5
Division of Genetics, Dept of Pediatrics, All India Institute of Medical Sciences RCV003235539 SCV003933700 likely pathogenic Osteogenesis imperfecta, perinatal lethal 2023-06-17 criteria provided, single submitter research
PreventionGenetics, part of Exact Sciences RCV004548123 SCV004103947 pathogenic COL1A1-related disorder 2023-10-03 criteria provided, single submitter clinical testing The COL1A1 c.1094G>T variant is predicted to result in the amino acid substitution p.Gly365Val. This variant was reported to be causative for osteogenesis imperfecta type II and documented de novo in two fetal cases (Table S1, Marini et al. 2007. PubMed ID: 17078022; Han et al. 2020. PubMed ID: 31994750; Bai et al. 2022. PubMed ID: 36352425). The p.Gly365 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

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