Variant summary: COL11A1 c.1630-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 3 acceptor site. This was further supported by a functional study where the authors have shown that this deletion altered the 3 acceptor splice site of the preceding intron leading to skipping of the 54bp exon from the mRNA (Martin_1999). The variant was absent in 250924 control chromosomes (gnomAD). c.1630-2delA has been reported in the literature in multiple individuals affected with Stickler syndrome (examples- Acke_2014, Martin_1999, Richards_2010) as well as in a patient with overlapping Marshall and Stickler syndrome phenotype (Annunen_1999). These data indicate that the variant is very likely to be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001854.4(COL11A1):c.1630-2del
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001854.4(COL11A1):c.1630-2del
Variation ID: 372792 Accession: VCV000372792.14
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 1p21.1 1: 103474074 (GRCh37) [ NCBI UCSC ] 1: 103008518 (GRCh38) [ 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 Jan 9, 2017 Apr 20, 2024 Mar 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001854.4:c.1630-2del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001190709.2:c.1513-2del splice acceptor NM_080629.3:c.1666-2del splice acceptor NM_080630.4:c.1282-2del splice acceptor NC_000001.11:g.103008518del NC_000001.10:g.103474074del NG_008033.2:g.104979del - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000001.11:103008517:T:
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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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| COL11A1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2674 | 2771 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 19, 2023 | RCV000413570.8 | |
| Pathogenic (1) |
criteria provided, single submitter
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Feb 7, 2020 | RCV001174947.1 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV001542539.7 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Feb 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Stickler syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338405.1
First in ClinVar: Jun 18, 2020 Last updated: Jun 18, 2020 |
Comment:
Variant summary: COL11A1 c.1630-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: COL11A1 c.1630-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 3 acceptor site. This was further supported by a functional study where the authors have shown that this deletion altered the 3 acceptor splice site of the preceding intron leading to skipping of the 54bp exon from the mRNA (Martin_1999). The variant was absent in 250924 control chromosomes (gnomAD). c.1630-2delA has been reported in the literature in multiple individuals affected with Stickler syndrome (examples- Acke_2014, Martin_1999, Richards_2010) as well as in a patient with overlapping Marshall and Stickler syndrome phenotype (Annunen_1999). These data indicate that the variant is very likely to be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000491292.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Destroys the canonical splice acceptor site in intron 14, and is expected to cause abnormal gene splicing; Not observed in large population cohorts (gnomAD); Using … (more)
Destroys the canonical splice acceptor site in intron 14, and is expected to cause abnormal gene splicing; Not observed in large population cohorts (gnomAD); Using fibroblast cDNA derived from patients harboring this variant, Martin et al. (1999) reported this variant results in the skipping of exon 15; the loss of the encoded residues is in the triple helical region and is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD; Acke et al., 2014); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); This variant is associated with the following publications: (PMID: 34680973, 34758253, 10486316, 15286167, 20513134, 25240749, 29453956, 28000701, 10573014) (less)
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Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318693.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. … (more)
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000372792, PMID:10573014). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present) , Mitral valve prolapse (present) , Retinal detachment (present) , Rod-cone dystrophy (present)
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Pathogenic
(Nov 19, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002228664.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a splice site in intron 14 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces altered … (more)
This sequence change affects a splice site in intron 14 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant Stickler syndrome (PMID: 10573014). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372792). Studies have shown that disruption of this splice site results in skipping of exon 15, but is expected to preserve the integrity of the reading-frame (PMID: 10573014). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 2
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806123.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Apr 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 2
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004814132.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The COL11A1 c.1630-2delA variant results in a substitution at the consensus splice acceptor site, which has been shown to cause skipping of exon 15 (Martin … (more)
The COL11A1 c.1630-2delA variant results in a substitution at the consensus splice acceptor site, which has been shown to cause skipping of exon 15 (Martin et al. 1999; Richards et al. 2010). The c.1630-2delA variant has been identified in a heterozygous state in at least six unrelated families with Stickler syndrome (Annunen et al. 1999; Martin et al. 1999; Richards et al. 2010; Acke et al. 2014). In one family, the c.1630-2delA variant was shown to segregate with disease among five affected individuals spanning three generations (Martin et al. 1999). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the collective evidence, the c.1630-2delA variant is classified as pathogenic for Stickler syndrome. (less)
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Pathogenic
(Oct 01, 1999)
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no assertion criteria provided
Method: literature only
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STICKLER SYNDROME, TYPE II
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038956.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 14, 2019 |
Comment on evidence:
In 2 families with Stickler syndrome and the type 2 (beaded) vitreous phenotype (STL2; 604841), Martin et al. (1999) found the causative mutation to be … (more)
In 2 families with Stickler syndrome and the type 2 (beaded) vitreous phenotype (STL2; 604841), Martin et al. (1999) found the causative mutation to be the substitution of a glycine residue in the collagen helix, likely to have a dominant-negative effect. The quantitatively minor type V and XI collagens form heterotypic fibrils with a more abundant type II fibrillar collagen and help to regulate fibril assembly and diameter. Type XI collagen is more abundant in tissues expressing type II collagen so it is to be expected that mutations in either COL2A1 or COL11A1 can cause Stickler syndrome. However, COL11A2 is not expressed in the vitreous, which explains why mutations in this gene give rise to some manifestations of Stickler syndrome but without eye anomalies (e.g., 120290.0001). In 1 family, analysis of cDNA between bases 930-1892 detected a deletion. Cloning and sequencing showed a loss of 54 bp from the RT-PCR product. Amplification and sequencing of this region of the gene showed that the 54 bp corresponded to a complete exon (gly16-gln33), which was present in both alleles of an affected individual. The 5-prime donor splice sequence of the following intron was found to be normal in both alleles. However, one allele had a single base deletion which altered the 3-prime acceptor splice site of the preceding intron, from consensus ag to tg. This led to skipping of the 54-bp exon from the mRNA. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Stickler syndrome type 2
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001759975.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
Comment:
Comment:
Destroys the canonical splice acceptor site in intron 14, and is expected to cause abnormal gene splicing; Not observed in large population cohorts (gnomAD); Using fibroblast cDNA derived from patients harboring this variant, Martin et al. (1999) reported this variant results in the skipping of exon 15; the loss of the encoded residues is in the triple helical region and is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD; Acke et al., 2014); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); This variant is associated with the following publications: (PMID: 34680973, 34758253, 10486316, 15286167, 20513134, 25240749, 29453956, 28000701, 10573014)
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000372792, PMID:10573014). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change affects a splice site in intron 14 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant Stickler syndrome (PMID: 10573014). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372792). Studies have shown that disruption of this splice site results in skipping of exon 15, but is expected to preserve the integrity of the reading-frame (PMID: 10573014). For these reasons, this variant has been classified as Pathogenic.
Comment:
The COL11A1 c.1630-2delA variant results in a substitution at the consensus splice acceptor site, which has been shown to cause skipping of exon 15 (Martin et al. 1999; Richards et al. 2010). The c.1630-2delA variant has been identified in a heterozygous state in at least six unrelated families with Stickler syndrome (Annunen et al. 1999; Martin et al. 1999; Richards et al. 2010; Acke et al. 2014). In one family, the c.1630-2delA variant was shown to segregate with disease among five affected individuals spanning three generations (Martin et al. 1999). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the collective evidence, the c.1630-2delA variant is classified as pathogenic for Stickler syndrome.
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:
Variant summary: COL11A1 c.1630-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 3 acceptor site. This was further supported by a functional study where the authors have shown that this deletion altered the 3 acceptor splice site of the preceding intron leading to skipping of the 54bp exon from the mRNA (Martin_1999). The variant was absent in 250924 control chromosomes (gnomAD). c.1630-2delA has been reported in the literature in multiple individuals affected with Stickler syndrome (examples- Acke_2014, Martin_1999, Richards_2010) as well as in a patient with overlapping Marshall and Stickler syndrome phenotype (Annunen_1999). These data indicate that the variant is very likely to be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Destroys the canonical splice acceptor site in intron 14, and is expected to cause abnormal gene splicing; Not observed in large population cohorts (gnomAD); Using fibroblast cDNA derived from patients harboring this variant, Martin et al. (1999) reported this variant results in the skipping of exon 15; the loss of the encoded residues is in the triple helical region and is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD; Acke et al., 2014); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); This variant is associated with the following publications: (PMID: 34680973, 34758253, 10486316, 15286167, 20513134, 25240749, 29453956, 28000701, 10573014)
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000372792, PMID:10573014). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change affects a splice site in intron 14 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant Stickler syndrome (PMID: 10573014). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372792). Studies have shown that disruption of this splice site results in skipping of exon 15, but is expected to preserve the integrity of the reading-frame (PMID: 10573014). For these reasons, this variant has been classified as Pathogenic.
Comment:
The COL11A1 c.1630-2delA variant results in a substitution at the consensus splice acceptor site, which has been shown to cause skipping of exon 15 (Martin et al. 1999; Richards et al. 2010). The c.1630-2delA variant has been identified in a heterozygous state in at least six unrelated families with Stickler syndrome (Annunen et al. 1999; Martin et al. 1999; Richards et al. 2010; Acke et al. 2014). In one family, the c.1630-2delA variant was shown to segregate with disease among five affected individuals spanning three generations (Martin et al. 1999). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the collective evidence, the c.1630-2delA variant is classified as pathogenic for Stickler syndrome.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing. | Acke FR | Molecular genetics and metabolism | 2014 | PMID: 25240749 |
| Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1. | Richards AJ | Human mutation | 2010 | PMID: 20513134 |
| Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity. | Martin S | European journal of human genetics : EJHG | 1999 | PMID: 10573014 |
| Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes. | Annunen S | American journal of human genetics | 1999 | PMID: 10486316 |
Text-mined citations for rs1057517989 ...
HelpThese 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 Sep 29, 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.