ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys)

dbSNP: rs72645347
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415259 SCV000492940 likely pathogenic Bruising susceptibility; Fragile skin; Joint hypermobility 2014-12-03 criteria provided, single submitter clinical testing
Invitae RCV000631472 SCV000752552 pathogenic Osteogenesis imperfecta type I 2023-04-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as 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 COL1A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17343). This missense change has been observed in individual(s) with EDS and Ehlers-Danlos syndrome (EDS) (PMID: 10739762, 17211858, 23587214, 25597651, 28102596). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 312 of the COL1A1 protein (p.Arg312Cys).
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198512 SCV001369472 likely pathogenic Osteogenesis imperfecta with normal sclerae, dominant form 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002276563 SCV002565547 pathogenic Ehlers-Danlos syndrome 2019-10-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496407 SCV002810468 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, arthrochalasia type; Osteogenesis imperfecta type I; Osteoporosis; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 2022-03-29 criteria provided, single submitter clinical testing
GeneDx RCV003225023 SCV003921700 pathogenic not provided 2022-10-31 criteria provided, single submitter clinical testing 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; Located in the Gly-Xaa-Yaa triple helical region of the pro-alpha1(I) chain encoded by the COL1A1 gene, where triplet glycine substitutions are the most common cause of osteogenesis imperfecta (OI). The effect of missense substitution at the X and Y positions are more difficult to predict; however, multiple variants that result in introduction of a Cys residue in pro-alpha1(I) have been reported to be pathogenic (Dalgleish, 1998); This variant is associated with the following publications: (PMID: 25597651, 10739762, 28102596, 30261568, 32736638, 9399846, 35587586, 35128800, 32369273, 31323331, 34265140, 34712265, 35205310, 35822426, 34484741, 35154279, 31531849)
CeGaT Center for Human Genetics Tuebingen RCV003225023 SCV004009814 pathogenic not provided 2023-06-01 criteria provided, single submitter clinical testing COL1A1: PP1:Strong, PM2, PM6, PS4:Moderate, PP2, PS3:Supporting
OMIM RCV000018884 SCV000039168 pathogenic Ehlers-Danlos syndrome, classic type 2000-04-01 no assertion criteria provided literature only
GeneReviews RCV000018884 SCV002600137 not provided Ehlers-Danlos syndrome, classic type no assertion provided literature only

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