NM_001844.5(COL2A1):c.1221+1G>A AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 8, 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:: RCV001377071.11

Allele description [Variation Report for NM_001844.5(COL2A1):c.1221+1G>A]

NM_001844.5(COL2A1):c.1221+1G>A

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.1221+1G>A

HGVS:

NC_000012.12:g.47987610C>T
NG_008072.1:g.21893G>A
NM_001844.5:c.1221+1G>AMANE SELECT
NM_033150.3:c.1014+1G>A
NC_000012.11:g.48381393C>T
NM_001844.4:c.1221+1G>A

Links:

dbSNP: rs1399741348

NCBI 1000 Genomes Browser:

rs1399741348

Molecular consequence:

NM_001844.5:c.1221+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_033150.3:c.1014+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001574304	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 20179744, 20513134, 31736238, 28492532
SCV001818909	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 8, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574304

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001818909

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 8, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574304.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change affects a donor splice site in intron 19 of the COL2A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL2A1 are known to be pathogenic (PMID: 20179744). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Stickler syndrome (PMID: 20179744, 20513134, 31736238; Invitae). ClinVar contains an entry for this variant (Variation ID: 866010). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

From GeneDx, SCV001818909.5

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

Description

Damages or destroys the splice donor site in intron 19, and is expected to cause abnormal gene splicing; if the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 36729443, 31736238, 20179744, 35791160)

#	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

Last Updated: Oct 13, 2024

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Relating variation to medicine