ClinVar Genomic variation as it relates to human health
NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)
Variation ID: 17366 Accession: VCV000017366.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.11 12: 47978329 (GRCh38) [ NCBI UCSC ] 12: 48372112 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Apr 15, 2024 Dec 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001844.5:c.2965C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001835.3:p.Arg989Cys missense NM_033150.3:c.2758C>T NP_149162.2:p.Arg920Cys missense NC_000012.12:g.47978329G>A NC_000012.11:g.48372112G>A NG_008072.1:g.31174C>T P02458:p.Arg989Cys - Protein change
- R920C, R989C
- Other names
- R789C
- Canonical SPDI
- NC_000012.12:47978328:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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COL2A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2808 | 2819 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000018910.33 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2023 | RCV000478360.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762895.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2022 | RCV000995718.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spondyloperipheral dysplasia
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002578929.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Sep 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568538.7
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 1
Multiple epiphyseal dysplasia, Beighton type Legg-Calve-Perthes disease Platyspondylic dysplasia, Torrance type Kniest dysplasia Spondyloepiphyseal dysplasia congenita Spondyloepimetaphyseal dysplasia, Strudwick type Achondrogenesis type II Spondyloperipheral dysplasia Namaqualand hip dysplasia Avascular necrosis of femoral head, primary, 1 Spondyloepiphyseal dysplasia with metatarsal shortening Stickler syndrome, type I, nonsyndromic ocular Spondyloepiphyseal dysplasia, Stanescu type
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893295.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(May 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Spondyloperipheral dysplasia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV001150043.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Dec 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001832237.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spondyloepiphyseal dysplasia congenita
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058184.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
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, PS1_S). The … (more)
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, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 8325895, 21924244, 25735649, PS4_S). The variant was co-segregated with SED congenita, associated with COL2A1 gene in multiple affected family members (PMID: 21924244, PP1_P) .In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.947, 3CNET: 0.956, PP3_P). A missense variant is a common mechanism associated with SED congenita (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. (less)
Clinical Features:
Lumbar hyperlordosis (present) , Lower limb asymmetry (present) , Rhizomelia (present) , Skeletal dysplasia (present) , Spondyloepimetaphyseal dysplasia (present)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Spondyloepiphyseal dysplasia congenita
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Suma Genomics
Accession: SCV004037036.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Age: 10-19 years
Sex: female
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Pathogenic
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001581179.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). 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 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. (less)
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Pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497588.12
First in ClinVar: Apr 08, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 1997)
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no assertion criteria provided
Method: literature only
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SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039194.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 17, 2017 |
Comment on evidence:
In a 4-year-old girl with clinical and radiographic features typical of SED congenita (183900), Chan et al. (1993) found heterozygosity for a 2913C-T transition in … (more)
In a 4-year-old girl with clinical and radiographic features typical of SED congenita (183900), Chan et al. (1993) found heterozygosity for a 2913C-T transition in exon 14, resulting in an arg789-to-cys (R789C) substitution. The mutation resulted in the loss of an MaeII cleavage site that was used to confirm the fact that the proband was heterozygous and that neither parent had the mutation. Type II collagen extracted from cartilage and from cultured chondrocytes was approximately one-third of the mutant type and secretion of molecules containing mutant chains was impaired. The thermal stability of the collagen extracted from cartilage was normal, however. In a patient with SED congenita, Chan et al. (1995) identified the R789C mutation. The substitution of a cysteine for an arginine in the Y position of the gly-X-Y triplet is noteworthy because cysteine is not normally found in the triple-helical domain of type II collagen in any species (Kuivaniemi et al., 1997). A cysteine at this position provides the opportunity for disulfide bonds to form, thus disrupting the formation of collagen fibrils. Two other arg-to-cys mutations have been described in the COL2A1 gene: R519C (120140.0003), resulting in osteoarthritis with mild chondrodysplasia (604864), and R75C (120140.0018), resulting in spondyloepiphyseal dysplasia with precocious osteoarthritis (609162). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Spondyloepiphyseal dysplasia congenita
Affected status: yes
Allele origin:
maternal
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002569961.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Six additional cases of SEDC due to the same and recurrent R989C mutation in the COL2A1 gene--the clinical and radiological follow-up. | Silveira KC | American journal of medical genetics. Part A | 2015 | PMID: 25735649 |
Identification of three novel mutations in the COL2A1 gene in four unrelated Chinese families with spondyloepiphyseal dysplasia congenita. | Zhang Z | Biochemical and biophysical research communications | 2011 | PMID: 21924244 |
Persistence of intracellular and extracellular changes after incompletely suppressing expression of the R789C (p.R989C) and R992C (p.R1192C) collagen II mutants. | Jensen DA | Human mutation | 2011 | PMID: 21472893 |
Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels. | Kuivaniemi H | Human mutation | 1997 | PMID: 9101290 |
Recurrent substitutions of arginine 789 by cysteine in pro-alpha 1 (II) collagen chains produce spondyloepiphyseal dysplasia congenita. | Chan D | The Journal of rheumatology. Supplement | 1995 | PMID: 7752132 |
Characterization of an arginine 789 to cysteine substitution in alpha 1 (II) collagen chains of a patient with spondyloepiphyseal dysplasia. | Chan D | The Journal of biological chemistry | 1993 | PMID: 8325895 |
Text-mined citations for rs121912874 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.