ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)

dbSNP: rs121912874
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478360 SCV000568538 pathogenic not provided 2022-09-12 criteria provided, single submitter clinical testing Functional studies using an inducible expression system for expressing p.(R989C) showed that even a small amount of the R989C mutant collagen would induce aberrations in the cell/matrix systems (Jensen et al., 2011); Located in the triple helical domain, a region of the protein in which cysteine residues are typically excluded (HGMD); 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; This variant is associated with the following publications: (PMID: 16155195, 9101290, 35250876, 25735649, 8325895, 21924244, 15895462, 7752132, 29354277, 21472893)
Fulgent Genetics, Fulgent Genetics RCV000762895 SCV000893295 pathogenic Achondrogenesis type II; Avascular necrosis of femoral head, primary, 1; Multiple epiphyseal dysplasia, Beighton type; Legg-Calve-Perthes disease; Kniest dysplasia; Namaqualand hip dysplasia; Spondyloperipheral dysplasia; Stickler syndrome type 1; Platyspondylic dysplasia, Torrance type; Spondylometaphyseal dysplasia; Spondyloepiphyseal dysplasia congenita; Spondyloepiphyseal dysplasia with metatarsal shortening; Stickler syndrome, type I, nonsyndromic ocular; Spondyloepiphyseal dysplasia, Stanescu type 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000995718 SCV001150043 pathogenic Spondyloperipheral dysplasia 2019-05-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000478360 SCV001581179 pathogenic not provided 2024-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 989 of the COL2A1 protein (p.Arg989Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant spondyloepiphyseal dysplasia congenita (PMID: 8325895, 21924244, 25735649). It has also been observed to segregate with disease in related individuals. This variant is also known as R789C. ClinVar contains an entry for this variant (Variation ID: 17366). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL2A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL2A1 function (PMID: 21472893). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000478360 SCV001832237 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing
3billion RCV005252114 SCV002058184 pathogenic Spondyloperipheral dysplasia; Spondyloepiphyseal dysplasia, Stanescu type 2024-02-20 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.73 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017366 /PMID: 8325895 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21924244, 25735649, 8325895). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 21924244). A different missense change at the same codon (p.Arg989Gly) has been reported to be associated with COL2A1 related disorder (PMID: 33908178). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen RCV000478360 SCV002497588 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000995718 SCV002578929 pathogenic Spondyloperipheral dysplasia 2022-06-14 criteria provided, single submitter clinical testing
Suma Genomics RCV000018910 SCV004037036 likely pathogenic Spondyloepiphyseal dysplasia congenita criteria provided, single submitter clinical testing
Baylor Genetics RCV000018910 SCV005049425 pathogenic Spondyloepiphyseal dysplasia congenita 2024-03-26 criteria provided, single submitter clinical testing
OMIM RCV000018910 SCV000039194 pathogenic Spondyloepiphyseal dysplasia congenita 1997-01-01 no assertion criteria provided literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000018910 SCV002569961 pathogenic Spondyloepiphyseal dysplasia congenita no assertion criteria provided clinical testing

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