ClinVar Miner

Submissions for variant NM_000089.4(COL1A2):c.1072G>A (p.Gly358Ser)

dbSNP: rs66619856
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002231005 SCV000627290 pathogenic Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 2022-11-29 criteria provided, single submitter clinical testing 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). 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. ClinVar contains an entry for this variant (Variation ID: 456802). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 16705691, 21520333, 22589248, 26371943, 26432670, 29150909; Invitae). 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 358 of the COL1A2 protein (p.Gly358Ser).
CeGaT Center for Human Genetics Tuebingen RCV001091391 SCV001247411 pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
GeneDx RCV001091391 SCV001771057 pathogenic not provided 2019-09-24 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); 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; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31299979, 16705691, 29150909, 21520333, 25525159, 26432670, 22589248, 26371943)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001542470 SCV001787150 pathogenic Osteogenesis imperfecta, perinatal lethal 2021-07-29 criteria provided, single submitter research ACMG codes: PS4M; PM1; PM2; PP3; PP5
3billion RCV001809476 SCV002058347 pathogenic Osteogenesis imperfecta type III 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000456802, PMID:16705691, PS1_S).The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29150909, 26432670, 26371943, 31299979, PS4_S). A different missense change at the same codon has been reported to be associated with COL1A2 related disorder (PMID:9240878,28116328, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.981, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Osteogenesis imperfecta (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV001809476 SCV002512407 pathogenic Osteogenesis imperfecta type III 2022-01-29 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM1 moderate, PM2 moderate, PM5, PP3 supporting, PP4 supporting
Fulgent Genetics, Fulgent Genetics RCV002490955 SCV002783179 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Osteoporosis; Ehlers-danlos syndrome, arthrochalasia type, 2; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 2021-07-13 criteria provided, single submitter clinical testing
Genomics England Pilot Project, Genomics England RCV001542470 SCV001760203 likely pathogenic Osteogenesis imperfecta, perinatal lethal no assertion criteria provided clinical testing

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