VCV000017368.37 - ClinVar

NM_001844.5(COL2A1):c.823C>T (p.Arg275Cys)

Germline

Classification

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.

(8)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001844.5(COL2A1):c.823C>T (p.Arg275Cys)

Variation ID: 17368 Accession: VCV000017368.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.11 12: 47994041 (GRCh38) [ NCBI UCSC ] 12: 48387824 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 4, 2013	May 12, 2024	Oct 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001844.5:c.823C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001835.3:p.Arg275Cys	missense
NM_033150.3:c.616C>T	NP_149162.2:p.Arg206Cys	missense
NC_000012.12:g.47994041G>A
NC_000012.11:g.48387824G>A
NG_008072.1:g.15462C>T
	P02458:p.Arg275Cys

... more HGVS ... less HGVS

Protein change

R206C, R275C

Other names

R75C

Canonical SPDI

NC_000012.12:47994040:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA127158 UniProtKB: P02458#VAR_001739 OMIM: 120140.0018 dbSNP: rs121912876 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
COL2A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2872	2884

Conditions - Germline

Condition Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Spondyloepiphyseal dysplasia with metatarsal shortening	Pathogenic (2)	criteria provided, single submitter	Sep 22, 2022	RCV000018912.35
Stickler syndrome type 1	Pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000988828.3
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 24, 2023	RCV001385337.12
Acetabular dysplasia	Pathogenic (1)	criteria provided, single submitter	-	RCV003228897.3
Achondrogenesis type II	Pathogenic (1)	criteria provided, single submitter	Jul 20, 2023	RCV003323361.2

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.
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Stickler syndrome type 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138713.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Pathogenic (Sep 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spondyloepiphyseal dysplasia with metatarsal shortening (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Additional submitter: CUBI - Core Unit Bioinformatics, Berlin Institute of Health Accession: SCV002574833.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Clinical Features: Premature osteoarthritis (present) , Hearing impairment (present) Sex: male Tissue: Blood
Pathogenic (Jan 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001814714.3 First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023	Comment: 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; … (more) 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; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 17368); This variant is associated with the following publications: (PMID: 21990059, 31633310, 31894489, 7757086, 16755660, 23928235, 23448908, 17726487, 31711313, 26183434, 15593085, 32071555, 31758797, 27234559, 28334714, 21204228, 26443184, 8877930, 26691295, 27523816, 16155195, 22791362, 21438135, 29738498, 25735649, 19433093, 21356074, 21472893, 18553548, 19764028, 21332586, 18383211, 8244341, 7738948, 8024616, 33706891, 30363003) (less)
Pathogenic (Jul 20, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Achondrogenesis type II Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029340.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (3) PubMed: 16755660‚ 19764028‚ 18553548 Comment: Variant summary: COL2A1 c.823C>T (p.Arg275Cys), also referred to by the legacy name Arg75Cys in the literature, results in a non-conservative amino acid change located in … (more) Variant summary: COL2A1 c.823C>T (p.Arg275Cys), also referred to by the legacy name Arg75Cys in the literature, results in a non-conservative amino acid change located in the collagen triple helix repeat region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250954 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with Czech Dysplasia from geographically distinct families where it has been found to segregate with the disease phenotype in an autosomal dominant, fully penetrant pattern of inheritance (e.g. Carlson_2006, Tzschach_2008, Matsui_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16755660, 19764028, 18553548). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Nov 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832467.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Acetabular dysplasia (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Rheumatology and Immunology Department, Shandong Provincial Hospital Affiliated to Shandong First Medicial University Accession: SCV002754582.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023	Clinical Features: Synovial chondromatosis (present) Sex: male
Pathogenic (Oct 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001585157.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 8244341‚ 32071555 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 275 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 275 of the COL2A1 protein (p.Arg275Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant COL2A1-related conditions (PMID: 8244341, 32071555). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg75Cys. ClinVar contains an entry for this variant (Variation ID: 17368). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 01, 2009)	no assertion criteria provided Method: literature only	CZECH DYSPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039196.5 First in ClinVar: Apr 04, 2013 Last updated: May 12, 2024	Publications: PubMed (4) PubMed: 8244341‚ 8024616‚ 17726487‚ 19764028 Comment on evidence: This mutation has also been designated arg275-to-cys (R275C) based on a different numbering system. In a family living in the Chiloe Islands, Chile, Williams et … (more) This mutation has also been designated arg275-to-cys (R275C) based on a different numbering system. In a family living in the Chiloe Islands, Chile, Williams et al. (1993) demonstrated a heterozygous arg75-to-cys (R75C) mutation in the COL2A1 gene as the basis of spondyloepiphyseal dysplasia with shortened metacarpals and metatarsals, precocious osteoarthritis, and periarticular apatite-like calcific deposits. Seven individuals were involved in 3 generations of the family. Complete physical examination, anthropometric measurements, and radiographic studies of the spine and peripheral joints in 16 family members revealed that 7 had spondyloepiphyseal dysplasia tarda, brachydactyly, precocious osteoarthritis, and periarticular calcification, while 2 others had the same syndrome without brachydactyly (Reginato et al., 1994). The relationship of this type of SEDT to familial calcium pyrophosphate dihydrate deposition disease (118600) and idiopathic hip dysplasia, both endemic in Chiloe Islanders, required further investigation. Hoornaert et al. (2007) performed targeted sequencing of exon 13 of the COL2A1 gene in patients with Czech dysplasia (609162) because of phenotypic similarities between individuals with this dysplasia and patients with the R75C mutation. They identified heterozygosity for the R75C mutation in 5 patients with Czech dysplasia, including 2 of the 4 original patients described with this disorder. All affected individuals had normal height, spondyloarthropathy, and short postaxial toes. In an affected father, daughter, and son from a Japanese family with Czech dysplasia, Matsui et al. (2009) identified heterozygosity for the R275C mutation in the COL2A1 gene. The mutation was not found in the unaffected mother. The authors stated that this was the first reported family with Czech dysplasia that was not of European ancestry, and family history was consistent with de novo occurrence of the disease in the father. (less)

Comment:

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; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 17368); This variant is associated with the following publications: (PMID: 21990059, 31633310, 31894489, 7757086, 16755660, 23928235, 23448908, 17726487, 31711313, 26183434, 15593085, 32071555, 31758797, 27234559, 28334714, 21204228, 26443184, 8877930, 26691295, 27523816, 16155195, 22791362, 21438135, 29738498, 25735649, 19433093, 21356074, 21472893, 18553548, 19764028, 21332586, 18383211, 8244341, 7738948, 8024616, 33706891, 30363003)

Comment:

Variant summary: COL2A1 c.823C>T (p.Arg275Cys), also referred to by the legacy name Arg75Cys in the literature, results in a non-conservative amino acid change located in the collagen triple helix repeat region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250954 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with Czech Dysplasia from geographically distinct families where it has been found to segregate with the disease phenotype in an autosomal dominant, fully penetrant pattern of inheritance (e.g. Carlson_2006, Tzschach_2008, Matsui_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16755660, 19764028, 18553548). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 275 of the COL2A1 protein (p.Arg275Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant COL2A1-related conditions (PMID: 8244341, 32071555). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg75Cys. ClinVar contains an entry for this variant (Variation ID: 17368). 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%. For these reasons, this variant has been classified as Pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and Molecular Characterization and Discovery of Novel Genetic Mutations of Chinese Patients with COL2A1-related Dysplasia.	Xu Y	International journal of biological sciences	2020	PMID: 32071555
Czech dysplasia occurring in a Japanese family.	Matsui Y	American journal of medical genetics. Part A	2009	PMID: 19764028
Czech dysplasia: report of a large family and further delineation of the phenotype.	Tzschach A	American journal of medical genetics. Part A	2008	PMID: 18553548
Czech dysplasia metatarsal type: another type II collagen disorder.	Hoornaert KP	European journal of human genetics : EJHG	2007	PMID: 17726487
Precocious osteoarthritis in a family with recurrent COL2A1 mutation.	Carlson KM	The Journal of rheumatology	2006	PMID: 16755660
Familial spondyloepiphyseal dysplasia tarda, brachydactyly, and precocious osteoarthritis associated with an arginine 75-->cysteine mutation in the procollagen type II gene in a kindred of Chiloe Islanders. I. Clinical, radiographic, and pathologic findings.	Reginato AJ	Arthritis and rheumatism	1994	PMID: 8024616
Spondyloepiphyseal dysplasia and precocious osteoarthritis in a family with an Arg75-->Cys mutation in the procollagen type II gene (COL2A1).	Williams CJ	Human genetics	1993	PMID: 8244341

Text-mined citations for rs121912876 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001844.5(COL2A1):c.823C>T (p.Arg275Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912876 ...