ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.3226G>A (p.Gly1076Ser) (rs67394386)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000596247 SCV000703178 pathogenic not provided 2016-11-21 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000490696 SCV000992540 pathogenic Osteogenesis imperfecta type III 2019-01-10 criteria provided, single submitter research ACMG codes: PS2, PS4, PM2, PP3, PP4, PP5
Invitae RCV001037391 SCV001200802 pathogenic Osteogenesis imperfecta type I 2020-05-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1076 of the COL1A1 protein (p.Gly1076Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with osteogenesis imperfecta (PMID:9101304, 26177859, 29499418, 29150909). In at least one individual the variant was observed to be de novo. This variant is also known as Gly898Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 425618). 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289611 SCV001477574 likely pathogenic none provided 2019-12-30 criteria provided, single submitter clinical testing The COL1A1 c.3226G>A; p.Gly1076Ser variant (rs67394386) is reported in the literature in multiple individuals who were affected with osteogenesis imperfect, and this variant was de novo in at least two of these individuals (Lindahl 2015, Lund 1997, Malmgren 2017, and Mrosk 2018). This variant is reported in ClinVar (Variation ID: 425618), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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). The glycine at codon 1076 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic.
Baylor Genetics RCV001330770 SCV001522562 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form 2019-12-24 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Medical Sciences,Uppsala University RCV000490696 SCV000574616 pathogenic Osteogenesis imperfecta type III no assertion criteria provided clinical testing

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