NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000481275.18

Allele description [Variation Report for NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter)]

NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter)

Gene:

COL2A1:collagen type II alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.11

Genomic location:

Preferred name:

NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter)

Other names:

R453*

HGVS:

NC_000012.12:g.47983721G>A
NG_008072.1:g.25782C>T
NM_001844.5:c.1957C>TMANE SELECT
NM_033150.3:c.1750C>T
NP_001835.3:p.Arg653Ter
NP_001835.3:p.Arg653Ter
NP_149162.2:p.Arg584Ter
NC_000012.11:g.48377504G>A
NM_001844.4:c.1957C>T
p.Arg453Ter

Protein change:

R584*; ARG453TER

Links:

OMIM: 120140.0045; dbSNP: rs121912893

NCBI 1000 Genomes Browser:

rs121912893

Molecular consequence:

NM_001844.5:c.1957C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033150.3:c.1750C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000568539	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 22, 2021)	germline	clinical testing	Citation Link,
SCV001832299	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Nov 30, 2019)	germline	clinical testing	Citation Link,
SCV002126178	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20179744, 12544472, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568539

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 22, 2021)

germline

clinical testing

Citation Link,

SCV001832299

Blueprint Genetics

criteria provided, single submitter

(Blueprint Genetics Variant Classification Scheme)

Pathogenic
(Nov 30, 2019)

germline

clinical testing

Citation Link,

SCV002126178

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 21, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

Hoornaert KP, Vereecke I, Dewinter C, Rosenberg T, Beemer FA, Leroy JG, Bendix L, Björck E, Bonduelle M, Boute O, Cormier-Daire V, De Die-Smulders C, Dieux-Coeslier A, Dollfus H, Elting M, Green A, Guerci VI, Hennekam RC, Hilhorts-Hofstee Y, Holder M, Hoyng C, Jones KJ, et al.

Eur J Hum Genet. 2010 Aug;18(8):872-80. doi: 10.1038/ejhg.2010.23. Epub 2010 Feb 24. Erratum in: Eur J Hum Genet. 2010 Aug;18(8):881.

PubMed [citation]

PMID:: 20179744
PMCID:: PMC2987380

The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1.

Liberfarb RM, Levy HP, Rose PS, Wilkin DJ, Davis J, Balog JZ, Griffith AJ, Szymko-Bennett YM, Johnston JJ, Francomano CA, Tsilou E, Rubin BI.

Genet Med. 2003 Jan-Feb;5(1):21-7. Review. Erratum in: Genet Med. 2003 Nov-Dec;5(6):478.

PubMed [citation]

PMID:: 12544472

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000568539.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported in multiple individuals with Stickler syndrome referred for genetic testing at GeneDx and in published literature (Wilkin et al., 2000; Liberfarb et al., 2003; Richards et al., 2005; Hoornaert et al., 2010; Richards et al., 2010; Savasta et al., 2015); Estimated to account for 2% of molecularly confirmed cases of Stickler syndrome type 1 (Barat-Houari et al., 2016); Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 17395; ClinVar); Also known as R453*; This variant is associated with the following publications: (PMID: 20179744, 20301479, 20513134, 16752401, 10982970, 26443184, 12544472, 12939326, 24164106, 25809783, 29453956, 15671297, 26747767)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Blueprint Genetics, SCV001832299.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002126178.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Arg653*) in the COL2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Stickler syndrome (PMID: 12544472). This variant is also known as p.R453X. ClinVar contains an entry for this variant (Variation ID: 17395). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 5, 2025

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