VCV000427128.14 - ClinVar

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

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.

(6)

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/Likely 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_001852.4(COL9A2):c.186G>A (p.Pro62=)

Variation ID: 427128 Accession: VCV000427128.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 40314352 (GRCh38) [ NCBI UCSC ] 1: 40780024 (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	Dec 9, 2017	Oct 8, 2024	Apr 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001852.4:c.186G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001843.1:p.Pro62=	synonymous
NC_000001.11:g.40314352C>T
NC_000001.10:g.40780024C>T
NG_008031.1:g.7916G>A

Protein change

Other names

Canonical SPDI

NC_000001.11:40314351:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA417331245 OMIM: 120260.0002 dbSNP: rs1085307973 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.
COL9A2		No evidence available	No evidence available	GRCh38 GRCh37	997	1054

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.
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 22, 2024	RCV000489270.15
Epiphyseal dysplasia, multiple, 2	Pathogenic (1)	no assertion criteria provided	Apr 1, 2010	RCV001807641.1
COL9A2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV004740263.1

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 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 (Jun 02, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450364.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 3
Pathogenic (Oct 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: SCV001832266.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
Pathogenic (Jan 04, 2024)	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: SCV001581361.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 10364514‚ 20358595‚ 21922596‚ 17576681‚ 9536098‚ 12244547 Comment: 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 … (more) 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. (less)
Likely pathogenic (Apr 22, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577760.8 First in ClinVar: May 22, 2017 Last updated: Sep 16, 2024	Comment: 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 … (more) 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) (less)
Pathogenic (Apr 01, 2010)	no assertion criteria provided Method: literature only	EPIPHYSEAL DYSPLASIA, MULTIPLE, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038964.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 09, 2017	Publications: PubMed (3) PubMed: 10364514‚ 15633184‚ 20358595 Comment on evidence: In family K of Holden et al. (1999) with multiple epiphyseal dysplasia-2 (EDM2; 600204), the proband was a 17-year-old male of normal height who was … (more) In family K of Holden et al. (1999) with multiple epiphyseal dysplasia-2 (EDM2; 600204), the proband was a 17-year-old male of normal height who was diagnosed in childhood with pain in the joints, mostly the knees, and genu varum. Radiographs showed major epiphyseal changes in the knees and hands, and almost no changes in the hips. The spine also appeared normal. The molecular change was a G-to-A transition in the last nucleotide of exon 3, changing the last codon of exon 3 from CCG (pro) to CCA (also pro). Although there was no change in the amino acid, the change interfered with splicing. Nakashima et al. (2005) identified the exon 3 G-to-A transition in the COL9A2 gene in affected members of a Japanese family with EDM2. The proband had bilateral double-layered patellae, indicating that this unusual feature is not unique to autosomal recessive multiple epiphyseal dysplasia with homozygous mutations in the DTDST gene (606718; see EDM4 226900). Jackson et al. (2010) reported a patient with EDM2 characterized by onset at age 3 years of an abnormal gait associated with proximal muscle weakness. He had left-sided developmental dysplasia of the hip. The family history was positive for hypodontia and for osteochondritis dissecans. However, 2 affected adult family members showed improvement of the disorder after puberty. The proband was heterozygous for the 186G-A transition in the splice donor sequence of exon 3 of the COL9A2 gene. (less)
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	COL9A2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360634.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The COL9A2 c.186G>A variant is not predicted to result in an amino acid change (p.=). This variant has been reported in individuals with multiple epiphyseal … (more) The COL9A2 c.186G>A variant is not predicted to result in an amino acid change (p.=). This variant has been reported in individuals with multiple epiphyseal dysplasia (MED) (Holden et al. 1999. PubMed ID: 10364514; Nakashima et al. 2005. PubMed ID: 15633184; Jackson et al. 2010. PubMed ID: 20358595). This variant is located at the last nucleotide of exon three and patient mRNA analysis suggested that this variant leads to the skipping of exon three (Holden et al. 1999. PubMed ID: 10364514). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. A different synonymous change impacting the same nucleotide (c.186G>C) has been reported to segregate with disease in a family with MED (Fiedler et al. 2002. PubMed ID: 12244547). The c.186G>A synonymous change is interpreted as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/427128/). Taken together, this variant is interpreted as pathogenic. (less)

Comment:

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.

Comment:

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)

Comment:

The COL9A2 c.186G>A variant is not predicted to result in an amino acid change (p.=). This variant has been reported in individuals with multiple epiphyseal dysplasia (MED) (Holden et al. 1999. PubMed ID: 10364514; Nakashima et al. 2005. PubMed ID: 15633184; Jackson et al. 2010. PubMed ID: 20358595). This variant is located at the last nucleotide of exon three and patient mRNA analysis suggested that this variant leads to the skipping of exon three (Holden et al. 1999. PubMed ID: 10364514). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. A different synonymous change impacting the same nucleotide (c.186G>C) has been reported to segregate with disease in a family with MED (Fiedler et al. 2002. PubMed ID: 12244547). The c.186G>A synonymous change is interpreted as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/427128/). Taken together, this variant is interpreted 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
Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.	Jackson GC	Human mutation	2012	PMID: 21922596
Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy.	Jackson GC	American journal of medical genetics. Part A	2010	PMID: 20358595
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation.	Nakashima E	American journal of medical genetics. Part A	2005	PMID: 15633184
Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2).	Fiedler J	American journal of medical genetics	2002	PMID: 12244547
Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia.	Holden P	American journal of human genetics	1999	PMID: 10364514
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs1085307973 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1085307973 ...