ClinVar Genomic variation as it relates to human health
NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys)
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.1693C>T (p.Arg565Cys)
Variation ID: 17383 Accession: VCV000017383.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.11 12: 47985575 (GRCh38) [ NCBI UCSC ] 12: 48379358 (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 Jan 9, 2017 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001844.5:c.1693C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001835.3:p.Arg565Cys missense NM_033150.3:c.1486C>T NP_149162.2:p.Arg496Cys missense NC_000012.12:g.47985575G>A NC_000012.11:g.48379358G>A NG_008072.1:g.23928C>T P02458:p.Arg565Cys - Protein change
- R496C, R565C
- Other names
- R365C
- Canonical SPDI
- NC_000012.12:47985574: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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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Jul 1, 2022 | RCV000018926.33 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000413561.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 6, 2020 | RCV001095763.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 6, 2019 | RCV001074673.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2016 | RCV001197973.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001807733.1 |
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
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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
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome, type I, nonsyndromic ocular
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058505.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 26747767, 27390512, 27390512, PS2_S). It has been observed in multiple … (more)
The variant has been previously reported as de novo in a similarly affected individual (PMID: 26747767, 27390512, 27390512, PS2_S). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 26747767, 27390512, 27390512, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.687, 3CNET: 0.905, PP3_P). A missense variant is a common mechanism associated with Stickler sydrome (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:
Buphthalmos (present) , Glaucoma of childhood (present) , Glaucoma (present) , Glaucoma of childhood (present) , Photophobia (present) , Primary congenital glaucoma (present) , Epiphora … (more)
Buphthalmos (present) , Glaucoma of childhood (present) , Glaucoma (present) , Glaucoma of childhood (present) , Photophobia (present) , Primary congenital glaucoma (present) , Epiphora (present) (less)
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Likely pathogenic
(Jul 01, 2022)
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criteria provided, single submitter
Method: research, in vitro
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Stickler syndrome type 1
Affected status: yes, not applicable
Allele origin:
inherited,
not applicable
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Center of Medical Genetics, Central South University
Accession: SCV002576563.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Observation 1:
Number of individuals with the variant: 7
Clinical Features:
High myopia (present) , vitreoretinal degeneration (present) , cataract (present) , midfacial hypoplasia (present) , sensorineural hearing loss (present) , joint hypermobility (present) , early-onset … (more)
High myopia (present) , vitreoretinal degeneration (present) , cataract (present) , midfacial hypoplasia (present) , sensorineural hearing loss (present) , joint hypermobility (present) , early-onset degenerative arthritis (present) (less)
Family history: yes
Secondary finding: no
Observation 2:
Method: The mutated COL2A1 plasmid was overexpressed in the Hela cell lines, then the COL2A1 aggregates and ER stress were evaluated by immunofluorenscen staining and western blot.
Result:
COL2A1 protein with the mutation tends to form aggregates and elevate ER stress in Hela cell lines.
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Pathogenic
(Feb 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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COL2A1-related disorders
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001251606.2
First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023 |
Comment:
The COL2A1 c.1693C>T (p.Arg565Cys) variant is a missense variant that has a well-documented association with Stickler syndrome. Across a selection of the available literature, this … (more)
The COL2A1 c.1693C>T (p.Arg565Cys) variant is a missense variant that has a well-documented association with Stickler syndrome. Across a selection of the available literature, this variant has been reported in a heterozygous state in at least eight affected individuals, including in a de novo state in one individual with confirmed parentage (Richards et al. 2000; Hoornaert et al. 2000; Wang et al. 2016; Zhou et al. 2018). This variant is not reported in the Genome Aggegation Database in a region of good sequencing coverage, indicating it is rare. The variant results in the substitution of a cysteine for an arginine in the X position of the Gly-X-Y repeat of the triple helical domain; this type of variant has been linked to ocular phenotypes. In addition to vitreous anomalies, myopia, and other ophthalmological anomalies, carriers of the p.Arg565Cys variant showed midface flattening, prominent eyes, low nasal bridge, and micrognathia. Mosaicism has been previously reported for COL2A1-related Stickler syndrome (Nagendran et al. 2012; Stevenson et al. 2012). Based on the cumulative evidence, the p.Arg565Cys variant is classified as pathogenic for COL2A1-related disorders. (less)
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Pathogenic
(Jul 07, 2023)
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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: SCV000491206.5
First in ClinVar: Jan 09, 2017 Last updated: Jul 16, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); Other missense variants that introduce a cysteine residue in the triple helical domain have been reported in association with COL2A1-related conditions (HGMD); This variant is associated with the following publications: (PMID: 26443184, 18309338, 32039712, 11007540, 20179744, 27390512, 21204228, 16155195, 20513134, 16752401, 28283280, 30181686, 29453956, 26747767, 31758797, 32112773, 30653986, 32756486, 34737199, 34680973, 24077912, 35473494) (less)
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Likely pathogenic
(Mar 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240266.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Likely pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Achondrogenesis type II
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368758.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP4,PP5.
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Likely pathogenic
(Dec 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 1
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556604.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766637.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Loss of function is associated with Stickler Syndrome while missense variants affecting glycine residue exert dominant-negative effect and is commonly associated with spondyloepiphyseal dysplasia (PMIDs: 15895462, 27234559). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial phenotypic variability and expressivity has been reported (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 16 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated triple-helical region (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Stickler (ClinVar, PMIDs: 16752401, 20179744). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 18, 2024)
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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: SCV001228620.5
First in ClinVar: Apr 15, 2020 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 565 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 565 of the COL2A1 protein (p.Arg565Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stickler syndrome or early onset high myopia (PMID: 11007540, 26747767, 27390512, 29453956). In at least one individual the variant was observed to be de novo. This variant is also known as R365C. ClinVar contains an entry for this variant (Variation ID: 17383). 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 not expected to disrupt COL2A1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2000)
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no assertion criteria provided
Method: literature only
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STICKLER SYNDROME, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039211.3
First in ClinVar: Apr 04, 2013 Last updated: May 19, 2017 |
Comment on evidence:
Richards et al. (2000) observed a recurrent arg365-to-cys (R365C) mutation of the COL2A1 gene in 2 unrelated sporadic cases of Stickler syndrome (STL1; 108300). The … (more)
Richards et al. (2000) observed a recurrent arg365-to-cys (R365C) mutation of the COL2A1 gene in 2 unrelated sporadic cases of Stickler syndrome (STL1; 108300). The mutation was located in the X position of the Gly-X-Y triple helical region and resulted in the membranous vitreous anomaly associated with haploinsufficiency. (less)
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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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Phenotypic characterization of patients with early-onset high myopia due to mutations in COL2A1 or COL11A1: Why not Stickler syndrome? | Zhou L | Molecular vision | 2018 | PMID: 30181686 |
Frequent mutations of RetNet genes in eoHM: Further confirmation in 325 probands and comparison with late-onset high myopia based on exome sequencing. | Zhou L | Experimental eye research | 2018 | PMID: 29453956 |
Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome. | Wang X | Molecular vision | 2016 | PMID: 27390512 |
Molecular genetics of the COL2A1-related disorders. | Deng H | Mutation research. Reviews in mutation research | 2016 | PMID: 27234559 |
Exome Sequencing on 298 Probands With Early-Onset High Myopia: Approximately One-Fourth Show Potential Pathogenic Mutations in RetNet Genes. | Sun W | Investigative ophthalmology & visual science | 2015 | PMID: 26747767 |
Mosaicism in Stickler syndrome. | Stevenson DA | European journal of medical genetics | 2012 | PMID: 22522174 |
Somatic mosaicism and the phenotypic expression of COL2A1 mutations. | Nagendran S | American journal of medical genetics. Part A | 2012 | PMID: 22496037 |
Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. | Hoornaert KP | European journal of human genetics : EJHG | 2010 | PMID: 20179744 |
High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. | Richards AJ | Human mutation | 2006 | PMID: 16752401 |
The phenotypic spectrum of COL2A1 mutations. | Nishimura G | Human mutation | 2005 | PMID: 15895462 |
Variation in the vitreous phenotype of Stickler syndrome can be caused by different amino acid substitutions in the X position of the type II collagen Gly-X-Y triple helix. | Richards AJ | American journal of human genetics | 2000 | PMID: 11007540 |
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Text-mined citations for rs121912884 ...
HelpRecord last updated Feb 20, 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.