ClinVar Genomic variation as it relates to human health
NM_004369.4(COL6A3):c.6210+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_004369.4(COL6A3):c.6210+1G>A
Variation ID: 94956 Accession: VCV000094956.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 237361120 (GRCh38) [ NCBI UCSC ] 2: 238269763 (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 Jun 28, 2015 Jun 9, 2024 Dec 5, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004369.4:c.6210+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_057166.5:c.4389+1G>A splice donor NM_057167.4:c.5592+1G>A splice donor NC_000002.12:g.237361120C>T NC_000002.11:g.238269763C>T NG_008676.1:g.58088G>A LRG_473:g.58088G>A LRG_473t1:c.6210+1G>A - Protein change
- Other names
- IVS16DS, G-A, +1
- Canonical SPDI
- NC_000002.12:237361119:C: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
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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
Help
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
Help
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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COL6A3 | - | - |
GRCh38 GRCh37 |
3208 | 3406 |
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. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2022 | RCV000080961.27 | |
Pathogenic (2) |
criteria provided, single submitter
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Sep 1, 2017 | RCV000175056.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 19, 2022 | RCV000817699.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 7, 2009 | RCV003764764.4 |
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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Pathogenic
(Jan 27, 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: SCV000331158.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ullrich congenital muscular dystrophy 1A
(Autosomal unknown)
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV000807203.2
First in ClinVar: Jun 28, 2015 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with a neuromuscular disorder: … (more)
This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 1-year-old female with a neuromuscular disorder: arthrogryposis, hypotonia, FTT, scoliosis, torticollis, fragile capillary syndrome. (less)
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Pathogenic
(Nov 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Bethlem myopathy 1A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000958277.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 16, … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 16, but is expected to preserve the integrity of the reading-frame (PMID: 15563506). ClinVar contains an entry for this variant (Variation ID: 94956). Disruption of this splice site has been observed in individual(s) with autosomal dominant Ullrich congenital muscular dystrophy (PMID: 15563506). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the COL6A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A3 are known to be disease-causing for autosomal recessive COL6A3 conditions (PMID: 21280092, 20976770). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL6A3 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL6A3-related conditions (PMID: 18366090). (less)
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Pathogenic
(Dec 05, 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: SCV000617316.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 17, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Different … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Different splice changes at this residue (c.6210+1G>C) and (c.6210+1G>T) and in nearby residues have been reported in the Human Gene Mutation Database and in the published literature (Stenson et al., 2014; D'Amico et al., 2017; Brias et al., 2010); This variant is associated with the following publications: (PMID: 25525159, 24907562, 15689448, 24314752, 18160674, 19015158, 22075033, 34167565, 34006472, 31127727, 35832501, 20301676, 18366090, 17785673, 20976770, 15563506) (less)
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Pathogenic
(Jul 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: SCV002064022.13
First in ClinVar: Jan 29, 2022 Last updated: May 12, 2024 |
Comment:
COL6A3: PS2:Very Strong, PVS1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954452.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jul 07, 2009)
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no assertion criteria provided
Method: literature only
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ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1C, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038975.5
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In a patient (UCMD5) with Ullrich congenital muscular dystrophy (UCMD1C; 620728), Baker et al. (2005) identified heterozygosity for a de novo splice site mutation (IVS16DS+1G-A) … (more)
In a patient (UCMD5) with Ullrich congenital muscular dystrophy (UCMD1C; 620728), Baker et al. (2005) identified heterozygosity for a de novo splice site mutation (IVS16DS+1G-A) in intron 16 of the COL6A3 gene. The mutation was predicted to result in loss of exon 16, which encodes amino acids 13 to 33 of the triple helical region of COL6A3. Nadeau et al. (2009) identified a recurrent de novo heterozygous IVS16DS+1G-A mutation in 2 unrelated patients with UCMD1C. The first patient was a 30-year-old individual who had onset at birth with hypotonia, congenital hip dislocation, delayed motor development, and feeding difficulties. Independent walking was not achieved, and the patient became wheelchair-bound at age 12 years. There was spinal rigidity, scoliosis, and kyphosis, as well as follicular hyperkeratosis, keloid formation, and need for nocturnal ventilation. The second patient had onset at age 1.5 years but never achieved independent walking and was wheelchair-bound by age 3.5 years. This patient died at age 10 years during a respiratory illness. (less)
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Pathogenic
(May 31, 2019)
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no assertion criteria provided
Method: research
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Ullrich congenital muscular dystrophy 1A
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: SCV001482341.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924211.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Bethlem myopathy 1A
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001519047.2
First in ClinVar: Mar 22, 2021 Last updated: Oct 01, 2022 |
Comment:
Common variant that results in exon 16 skipping
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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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Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies. | Fan Y | Clinical genetics | 2018 | PMID: 29419890 |
siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy. | Bolduc V | Molecular therapy. Nucleic acids | 2014 | PMID: 24518369 |
Natural history of pulmonary function in collagen VI-related myopathies. | Foley AR | Brain : a journal of neurology | 2013 | PMID: 24271325 |
Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy. | Foley AR | Annals of neurology | 2011 | PMID: 21280092 |
Early onset collagen VI myopathies: Genetic and clinical correlations. | Briñas L | Annals of neurology | 2010 | PMID: 20976770 |
Natural history of Ullrich congenital muscular dystrophy. | Nadeau A | Neurology | 2009 | PMID: 19564581 |
Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance. | Lampe AK | Human mutation | 2008 | PMID: 18366090 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. | Baker NL | Human molecular genetics | 2005 | PMID: 15563506 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A3 | - | - | - | - |
Text-mined citations for rs398124126 ...
HelpRecord last updated Jun 10, 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.