This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 28424332]
ClinVar Genomic variation as it relates to human health
NM_001848.3(COL6A1):c.930+189C>T
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.
(9)
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
9
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_001848.3(COL6A1):c.930+189C>T
Variation ID: 542998 Accession: VCV000542998.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 45989967 (GRCh38) [ NCBI UCSC ] 21: 47409881 (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 Oct 10, 2018 Feb 20, 2024 Jan 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001848.3:c.930+189C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000021.9:g.45989967C>T NC_000021.8:g.47409881C>T NG_008674.1:g.13219C>T LRG_475:g.13219C>T LRG_475t1:c.930+189C>T - Protein change
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- Other names
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- Canonical SPDI
- NC_000021.9:45989966: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
Help
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
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| 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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| COL6A1 | - | - |
GRCh38 GRCh37 |
1782 | 1894 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2024 | RCV000653589.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 30, 2023 | RCV000728981.7 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2023 | RCV001334958.5 |
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
(Jun 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Bethlem myopathy 1A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000837714.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Ventriculomegaly (present) , Muscular Diseases (present) , Muscle weakness (present) , Muscle fiber hypertrophy (present) , Loss of ability to walk in early childhood (present) … (more)
Ventriculomegaly (present) , Muscular Diseases (present) , Muscle weakness (present) , Muscle fiber hypertrophy (present) , Loss of ability to walk in early childhood (present) , Loss of ability to walk (present) , Knee flexion contracture (present) , Infantile muscular hypotonia (present) , Generalized hypotonia (present) , Flexion contracture (present) , Fatty replacement of skeletal muscle (present) , Elbow flexion contracture (present) , Delayed gross motor development (present) , Cryptorchidism (present) , Ankle contracture (present) , Abnormality of muscle fibers (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Mexican
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-06-07
Testing laboratory interpretation: Likely pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Wrist flexion contracture (present) , Type 2 muscle fiber atrophy (present) , Toe walking (present) , Progressive muscle weakness (present) , Poor eye contact (present) … (more)
Wrist flexion contracture (present) , Type 2 muscle fiber atrophy (present) , Toe walking (present) , Progressive muscle weakness (present) , Poor eye contact (present) , Muscular Diseases (present) , Knee flexion contracture (present) , Intellectual disability (present) , Hyperpigmented nevi and streak (present) , Hyperextensibility of the finger joints (present) , Hip contracture (present) , Gowers sign (present) , Global developmental delay (present) , Generalized amyotrophy (present) , Gait disturbance (present) , Flexion contracture of finger (present) , Elbow flexion contracture (present) , Dry skin (present) , Difficulty climbing stairs (present) , Delayed speech and language development (present) , Decreased serum creatinine (present) , Cafe-au-lait spot (present) , Autistic disorder of childhood onset (present) , Areflexia (present) , Ankle contracture (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hispanic or Latino
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2018-05-08
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Feb 15, 2018)
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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: SCV000856611.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(May 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Ullrich congenital muscular dystrophy 1A
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001527974.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 28424332]
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Pathogenic
(Oct 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Bethlem myopathy 1A
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579659.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM4, PM6, PM2_SUP, PP1
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jan 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ullrich congenital muscular dystrophy 1A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003525941.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Clinical Features:
Generalized hypotonia (present) , Muscle weakness (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Inability to walk (present) , Congenital contracture (present) , … (more)
Generalized hypotonia (present) , Muscle weakness (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Inability to walk (present) , Congenital contracture (present) , Multiple joint contractures (present) , Spinal rigidity (present) (less)
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Pathogenic
(May 30, 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: SCV001803075.2
First in ClinVar: Aug 21, 2021 Last updated: Jun 10, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as c.930+189 C>T creates a cryptic splice donor site which pairs with a cryptic splice acceptor site 72 … (more)
Published functional studies demonstrate a damaging effect as c.930+189 C>T creates a cryptic splice donor site which pairs with a cryptic splice acceptor site 72 base pairs upstream, resulting in the inclusion of a pseudoexon of 24 amino acids within the well conserved N-terminal triple-helical G-X-Y repeat region of COL6A1, where disruption has been associated with pathogenicity (Cummings et al., 2017); No data available from ethnically-matched control populations to assess the frequency of this variant; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34758253, 28424332, 30659139, 30895940, 31607746, 34167565, 37023487, 33441455, 32585628, 33977145) (less)
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Pathogenic
(Jan 10, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000775472.8
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 11 of the COL6A1 gene. It does not directly change the encoded amino acid sequence of the COL6A1 protein. … (more)
This sequence change falls in intron 11 of the COL6A1 gene. It does not directly change the encoded amino acid sequence of the COL6A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 24 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal dominant collagen VI–related dystrophy (PMID: 28424332). In at least one individual the variant was observed to be de novo. This variant is also known as chr21: 47,409,881 C>T. ClinVar contains an entry for this variant (Variation ID: 542998). Studies have shown that this variant results in the activation of a cryptic splice site in intron 11 (PMID: 28424332). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Ullrich congenital muscular dystrophy 1A
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760478.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 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: SCV001519044.2
First in ClinVar: Mar 22, 2021 Last updated: Oct 01, 2022 |
Comment:
Common variant in intron 11 that induces an in-frame pseudoexon insertion
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect as c.930+189 C>T creates a cryptic splice donor site which pairs with a cryptic splice acceptor site 72 base pairs upstream, resulting in the inclusion of a pseudoexon of 24 amino acids within the well conserved N-terminal triple-helical G-X-Y repeat region of COL6A1, where disruption has been associated with pathogenicity (Cummings et al., 2017); No data available from ethnically-matched control populations to assess the frequency of this variant; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34758253, 28424332, 30659139, 30895940, 31607746, 34167565, 37023487, 33441455, 32585628, 33977145)
Comment:
This sequence change falls in intron 11 of the COL6A1 gene. It does not directly change the encoded amino acid sequence of the COL6A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 24 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal dominant collagen VI–related dystrophy (PMID: 28424332). In at least one individual the variant was observed to be de novo. This variant is also known as chr21: 47,409,881 C>T. ClinVar contains an entry for this variant (Variation ID: 542998). Studies have shown that this variant results in the activation of a cryptic splice site in intron 11 (PMID: 28424332). For these reasons, this variant has been classified as Pathogenic.
Comment:
Common variant in intron 11 that induces an in-frame pseudoexon insertion
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:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 28424332]
Comment:
Published functional studies demonstrate a damaging effect as c.930+189 C>T creates a cryptic splice donor site which pairs with a cryptic splice acceptor site 72 base pairs upstream, resulting in the inclusion of a pseudoexon of 24 amino acids within the well conserved N-terminal triple-helical G-X-Y repeat region of COL6A1, where disruption has been associated with pathogenicity (Cummings et al., 2017); No data available from ethnically-matched control populations to assess the frequency of this variant; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34758253, 28424332, 30659139, 30895940, 31607746, 34167565, 37023487, 33441455, 32585628, 33977145)
Comment:
This sequence change falls in intron 11 of the COL6A1 gene. It does not directly change the encoded amino acid sequence of the COL6A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 24 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal dominant collagen VI–related dystrophy (PMID: 28424332). In at least one individual the variant was observed to be de novo. This variant is also known as chr21: 47,409,881 C>T. ClinVar contains an entry for this variant (Variation ID: 542998). Studies have shown that this variant results in the activation of a cryptic splice site in intron 11 (PMID: 28424332). For these reasons, this variant has been classified as Pathogenic.
Comment:
Common variant in intron 11 that induces an in-frame pseudoexon insertion
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies. | Bolduc V | JCI insight | 2019 | PMID: 30895940 |
| Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. | Cummings BB | Science translational medicine | 2017 | PMID: 28424332 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A1 | - | - | - | - |
Text-mined citations for rs1556425596 ...
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.