ClinVar Genomic variation as it relates to human health
NM_001854.4(COL11A1):c.3816+1G>A
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001854.4(COL11A1):c.3816+1G>A
Variation ID: 39776 Accession: VCV000039776.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p21.1 1: 102915630 (GRCh38) [ NCBI UCSC ] 1: 103381186 (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 23, 2015 Feb 14, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001854.4:c.3816+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001190709.2:c.3699+1G>A splice donor NM_080629.3:c.3852+1G>A splice donor NM_080630.4:c.3468+1G>A splice donor NC_000001.11:g.102915630C>T NC_000001.10:g.103381186C>T NG_008033.2:g.197867G>A - Protein change
- Other names
- IVS50, G-A, +1
- Canonical SPDI
- NC_000001.11:102915629:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- exon loss Variation Ontology [VariO:0381]
- PubMed: 17236192
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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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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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COL11A1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2595 | 2689 |
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
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
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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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Pathogenic (2) |
no assertion criteria provided
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May 31, 2019 | RCV000032995.34 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV000579344.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 2, 2016 | RCV000623510.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 22, 2021 | RCV002468558.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2023 | RCV003313929.1 |
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
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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
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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Pathogenic
(Aug 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV002817261.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The majority of patients reported with this variant are described as having Marshall syndrome (PMID 17236192, 9529347, 19449424, 3002026, 25073711) although some are also described … (more)
The majority of patients reported with this variant are described as having Marshall syndrome (PMID 17236192, 9529347, 19449424, 3002026, 25073711) although some are also described as having Stickler syndrome (PMID 97928857, 25240749). This variant segregates with disease in multiple families (PMID 9529347, 30020262, 25073711). Computational tools yielded predictions that this variant may interfere with normal RNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Pathogenic
(Jun 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741536.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Frontal bossing (present) , Laryngotracheomalacia (present) , Secundum atrial septal defect (present) , Patent foramen ovale (present) , Failure to thrive (present) , Disproportionate short … (more)
Frontal bossing (present) , Laryngotracheomalacia (present) , Secundum atrial septal defect (present) , Patent foramen ovale (present) , Failure to thrive (present) , Disproportionate short stature (present) , Broad face (present) , Hypertelorism (present) , Shallow orbits (present) , Short nose (present) , Wide anterior fontanel (present) , Abnormality of finger (present) , Feeding difficulties (present) , Vomiting (present) , Global developmental delay (present) , Anteverted nares (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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COL11A1-related disorder
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004013169.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PS4, PM2, PM6, PP1, PP3_Strong
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Pathogenic
(Sep 29, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000335759.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Stickler syndrome type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764981.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the face (present) , Hearing abnormality (present) , Hypertelorism (present)
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Pathogenic
(Apr 13, 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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GeneDx
Accession: SCV000680761.3
First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing; sequencing of cDNA prepared from patient fibroblasts demonstrated in-frame deletion of 18 amino acid codons … (more)
Canonical splice site variant expected to result in aberrant splicing; sequencing of cDNA prepared from patient fibroblasts demonstrated in-frame deletion of 18 amino acid codons in the triple helical domain, consistent with exon skip (Griffith et al., 1998); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17236192, 34589056, 19449424, 25240749, 25525159, 9529347, 28983407, 25073711, 30020262, 33502061, 34006472, 33951325) (less)
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Pathogenic
(Oct 23, 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: SCV002233649.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 50 of the COL11A1 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 50 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 Marshall or Stickler syndrome (PMID: 9529347, 19449424, 25240749). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS50+1G>A. ClinVar contains an entry for this variant (Variation ID: 39776). Studies have shown that disruption of this splice site results in skipping of exon 51, but is expected to preserve the integrity of the reading-frame (PMID: 9529347). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2007)
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no assertion criteria provided
Method: literature only
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MARSHALL SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038953.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 14, 2019 |
Comment on evidence:
In a large 3-generation kindred with Marshall syndrome (MRSHS; 154780), Griffith et al. (1998) demonstrated a splice site mutation in the COL11A1 gene in affected … (more)
In a large 3-generation kindred with Marshall syndrome (MRSHS; 154780), Griffith et al. (1998) demonstrated a splice site mutation in the COL11A1 gene in affected individuals. A G-to-A transition at the 5-prime end of an intron caused in-frame skipping of the preceding 54-bp exon and deletion of amino acids 726 to 743 from the major triple helical domain of the alpha-1(XI) collagen polypeptide. Shanske et al. (1998) suggested that the family reported by Griffith et al. (1998) suffered from Stickler syndrome (STL2; 604841), not Marshall syndrome. Shanske et al. (1997) reported a family in which 6 members in 4 generations were affected with Marshall syndrome. From a review of the literature, they attempted to distinguish the Stickler and Marshall syndromes. In both disorders, ophthalmologic abnormalities including high myopia, as well as midfacial hypoplasia, micrognathia with or without palatal clefting, and nonspecific skeletal abnormalities have been reported. In spite of these overlaps, each of the disorders has distinctive features. Striking ocular hypertelorism and abnormalities of ectodermal derivatives had been reported only in Marshall syndrome. The phenotype described by Griffith et al. (1998) included only 'mild' orbital hypertelorism and no evidence of ectodermal derivative abnormalities. Warman et al. (1998) vigorously defended the diagnosis of Marshall syndrome in the family they reported (Griffith et al., 1998). They argued that a comparison of the principal findings reported by Marshall (1958) with the findings in their family revealed high concordance, whereas comparison with the patients reported by Shanske et al. (1997) showed low concordance. Marshall's patients and their patients all had congenital or juvenile cataracts and fluid vitreous; none of the patients described by Shanske et al. (1997) had these conditions. Marshall's patients and their patients all had significant hearing loss; none of the patients described by Shanske et al. (1997) had hearing loss. Marshall's patients had 'ample and normal hair,' as did their patients; the patients described by Shanske et al. (1997) all had 'sparse' hair or a 'paucity of hair.' Two of Marshall's patients were studied radiographically; each had nasal bones that were 'small, short, and far back of their normal position.' These patients also had 'prominence of the frontal bossae,' which served to 'accentuate the flatness or depression of the bridge of the nose,' and 'thickening of the outer table of the skull and absent frontal sinuses.' In their report (Griffith et al., 1998), a patient photograph and cranial CT scan were included that showed nearly identical features. In contrast, the patients described by Shanske et al. (1997) had 'significant frontal recession' and normal skeletal surveys. Warman et al. (1998) pointed out that although the presence of ectodermal abnormalities in the patients of Marshall (1958) had been emphasized, e.g., sparse hair, eyebrows, and eyelashes, the patients, in fact, did not have these; instead, Marshall (1958) thought that his patients had an altered ability to sweat. When comparing his patients with a 32-year-old female control, Marshall (1958) observed that sweat production was 'diminished, perhaps 25% below normal.' In 3 unrelated patients with Marshall syndrome, Majava et al. (2007) identified heterozygosity for the 54-bp deletion of exon 50. All 3 patients had severe midface hypoplasia with a short nose, anteverted nares, and bulging eyes; sensorineural hearing loss was confirmed in the 2 patients who were old enough to test. No signs of ectodermal dysplasia were observed. (less)
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Pathogenic
(May 31, 2019)
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no assertion criteria provided
Method: research
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Marshall syndrome
Affected status: yes
Allele origin:
de novo
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Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Accession: SCV001482318.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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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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Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing. | Acke FR | Molecular genetics and metabolism | 2014 | PMID: 25240749 |
Mosaicism in Marshall syndrome. | Ala-Kokko L | American journal of medical genetics. Part A | 2009 | PMID: 19449424 |
A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype-phenotype correlations in type XI collagenopathies. | Majava M | American journal of medical genetics. Part A | 2007 | PMID: 17236192 |
Marshall syndrome and a defect at the COL11A1 locus. | Shanske A | American journal of human genetics | 1998 | PMID: 9792885 |
Marshall syndrome associated with a splicing defect at the COL11A1 locus. | Griffith AJ | American journal of human genetics | 1998 | PMID: 9529347 |
The Marshall syndrome: report of a new family and review of the literature. | Shanske AL | American journal of medical genetics | 1997 | PMID: 9129742 |
Ectodermal dysplasia; report of kindred with ocular abnormalities and hearing defect. | MARSHALL D | American journal of ophthalmology | 1958 | PMID: 13520885 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL11A1 | - | - | - | - |
Warman, M. L., Tiller, G. E., Griffith, A. J. Reply to Shanske et al. (Letter) Am. J. Hum. Genet. 63: 1559-1561, 1998. | - | - | - | - |
Text-mined citations for rs398122828 ...
HelpRecord last updated Apr 20, 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.