NM_001852.4(COL9A2):c.186G>A (p.Pro62=) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Apr 22, 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:: RCV000489270.15

Allele description [Variation Report for NM_001852.4(COL9A2):c.186G>A (p.Pro62=)]

NM_001852.4(COL9A2):c.186G>A (p.Pro62=)

Gene:

COL9A2:collagen type IX alpha 2 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_001852.4(COL9A2):c.186G>A (p.Pro62=)

HGVS:

NC_000001.11:g.40314352C>T
NG_008031.1:g.7916G>A
NM_001852.4:c.186G>AMANE SELECT
NP_001843.1:p.Pro62=
NC_000001.10:g.40780024C>T
NM_001852.3:c.186G>A

Links:

OMIM: 120260.0002; dbSNP: rs1085307973

NCBI 1000 Genomes Browser:

rs1085307973

Molecular consequence:

NM_001852.4:c.186G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

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
SCV000577760	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 22, 2024)	germline	clinical testing	Citation Link,
SCV001450364	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 2, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001581361	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20358595, 21922596, 17576681, 9536098, 10364514, 12244547, 28492532
SCV001832266	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Oct 30, 2019)	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	3	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy.

Jackson GC, Marcus-Soekarman D, Stolte-Dijkstra I, Verrips A, Taylor JA, Briggs MD.

Am J Med Genet A. 2010 Apr;152A(4):863-9. doi: 10.1002/ajmg.a.33240.

PubMed [citation]

PMID:: 20358595
PMCID:: PMC3557369

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000577760.8

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

Description

Published functional studies demonstrate altered mRNA splicing (PMID: 10364514); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21922596, 31589614, 9536098, 17576681, 33726816, 20358595, 10364514)

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450364.1

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

#	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		3	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001581361.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change affects codon 62 of the COL9A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL9A2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individuals with autosomal dominant multiple epiphyseal dysplasia (PMID: 10364514, 20358595, 21922596). ClinVar contains an entry for this variant (Variation ID: 427128). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 10364514). This variant disrupts the c.186G nucleotide in the COL9A2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12244547; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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 Blueprint Genetics, SCV001832266.1

#	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

Last Updated: Oct 13, 2024

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