ClinVar Genomic variation as it relates to human health
NM_001852.4(COL9A2):c.1242del (p.Gly415fs)
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.
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(2); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001852.4(COL9A2):c.1242del (p.Gly415fs)
Variation ID: 632106 Accession: VCV000632106.18
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 1p34.2 1: 40304365 (GRCh38) [ NCBI UCSC ] 1: 40770037 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 27, 2019 May 12, 2024 Sep 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001852.4:c.1242del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001843.1:p.Gly415fs frameshift NM_001852.3:c.1242del NM_001852.3:c.1242delC NC_000001.11:g.40304371del NC_000001.10:g.40770043del NG_008031.1:g.17903del - Protein change
- G415fs
- Other names
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- Canonical SPDI
- NC_000001.11:40304364:GGGGGGG:GGGGGG
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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COL9A2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
985 | 1041 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000778980.5 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2023 | RCV001873178.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 5, 2023 | RCV003396351.4 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Uncertain significance
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome, type 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915411.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The COL9A2 c.1242delC (p.Gly415GlufsTer116) variant results in a frameshift, and is predicted to result in premature termination of the protein. It was observed by ICSL … (more)
The COL9A2 c.1242delC (p.Gly415GlufsTer116) variant results in a frameshift, and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive Stickler syndrome. (less)
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Likely pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003842596.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge (less)
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Uncertain significance
(Sep 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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COL9A2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103101.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The COL9A2 c.1242delC variant is predicted to result in a frameshift and premature protein termination (p.Gly415Glufs*116). This variant was reported in the homozygous state in … (more)
The COL9A2 c.1242delC variant is predicted to result in a frameshift and premature protein termination (p.Gly415Glufs*116). This variant was reported in the homozygous state in an individual with clinical features consistent with Stickler syndrome. The described patient, who had consanguineous parents, also had features consistent with an immune disorder and was homozygous for possibly causative variants in both AK2 and ATM (Ichikawa et al. 2020. PubMed ID: 32532877). This variant is reported in 0.015% of alleles in individuals of African descent in gnomAD, although gnomAD quality metrics indicate the data quality may be low at this site and therefore allele frequencies should be interpreted with caution (http://gnomad.broadinstitute.org/variant/1-40770036-CG-C). While we suspect this variant may be pathogenic for autosomal recessive COL9A2-related Stickler syndrome, it is less likely to be causative for autosomal dominant multiple epiphyseal dysplasia, which is typically associated with variants impacting nucleotide c.186 or the adjacent splice donor site (Human Gene Mutation Database, HGMD). (less)
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Pathogenic
(Aug 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002208316.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly415Glufs*116) in the COL9A2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gly415Glufs*116) in the COL9A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL9A2 are known to be pathogenic (PMID: 21671392, 33356723). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL9A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 632106). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821022.9
First in ClinVar: Jan 21, 2023 Last updated: May 12, 2024 |
Comment:
COL9A2: PVS1, PM2, PM3:Supporting
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Autosomal recessive Stickler syndrome associated with homozygous mutations in the COL9A2 gene. | Kjellström U | Ophthalmic genetics | 2021 | PMID: 33356723 |
A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. | Baker S | American journal of medical genetics. Part A | 2011 | PMID: 21671392 |
Text-mined citations for rs756694568 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.