Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 27884173, 34426522, 30011071, 33471381, 35276021, 37431644, 37883475, 32802955, 37692655, 25059916, 20164846)
ClinVar Genomic variation as it relates to human health
NM_001723.7(DST):c.3370C>T (p.Gln1124Ter)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001723.7(DST):c.3370C>T (p.Gln1124Ter)
Variation ID: 66012 Accession: VCV000066012.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.1 6: 56620664 (GRCh38) [ NCBI UCSC ] 6: 56485462 (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 3, 2013 Oct 26, 2024 Oct 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001374736.1:c.4929+3866C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001723.7:c.3370C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001714.1:p.Gln1124Ter nonsense NM_001144769.5:c.4830+3866C>T intron variant NM_001144770.2:c.4416+3866C>T intron variant NM_001374722.1:c.4929+3866C>T intron variant NM_001374729.1:c.4296+3866C>T intron variant NM_001374730.1:c.4296+3866C>T intron variant NM_001374734.1:c.4956+3866C>T intron variant NM_001386100.1:c.4296+3866C>T intron variant NM_015548.5:c.3318+3866C>T intron variant NM_183380.4:c.4296+3866C>T intron variant NC_000006.12:g.56620664G>A NC_000006.11:g.56485462G>A NG_029322.2:g.338965C>T - Protein change
- Q1124*
- Other names
- -
- Canonical SPDI
- NC_000006.12:56620663:G:A
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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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Exome Aggregation Consortium (ExAC) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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. |
|||
| DST | - | - | GRCh38 | 3755 | 3838 | |
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
|
Jun 6, 2024 | RCV000056254.40 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 15, 2024 | RCV000437664.15 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
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May 21, 2024 | RCV000454900.13 | |
| Pathogenic (1) |
criteria provided, single submitter
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Oct 18, 2023 | RCV000803078.17 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Mar 25, 2024 | RCV003447111.4 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005049802.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Oct 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000516007.6
First in ClinVar: Mar 08, 2017 Last updated: Oct 26, 2024 |
Comment:
Nonsense 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)
Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 27884173, 34426522, 30011071, 33471381, 35276021, 37431644, 37883475, 32802955, 37692655, 25059916, 20164846) (less)
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Pathogenic
(Dec 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021804.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Hereditary sensory and autonomic neuropathy type 6
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000942936.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1124*) in the DST gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln1124*) in the DST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DST are known to be pathogenic (PMID: 22522446, 25059916, 30371979). This variant is present in population databases (rs201045495, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with epidermolysis bullosa simplex (PMID: 20164846, 25059916). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66012). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary sensory and autonomic neuropathy type 6
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806082.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005049508.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Clinical Features:
Pyoderma (present) , Lamina lucida cleavage (present) , Abnormal blistering of the skin (present)
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Likely pathogenic
(Oct 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469255.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(Jun 01, 2010)
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no assertion criteria provided
Method: literature only
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EPIDERMOLYSIS BULLOSA SIMPLEX 3, LOCALIZED OR GENERALIZED INTERMEDIATE, WITH BP230 DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000087426.3
First in ClinVar: Oct 03, 2013 Last updated: Feb 13, 2022 |
Comment on evidence:
In a 38-year-old Kuwaiti man with autosomal recessive epidermolysis bullosa simplex-3 with BP 230 deficiency (EBS3; 615425), Groves et al. (2010) identified a homozygous c.3478C-T … (more)
In a 38-year-old Kuwaiti man with autosomal recessive epidermolysis bullosa simplex-3 with BP 230 deficiency (EBS3; 615425), Groves et al. (2010) identified a homozygous c.3478C-T transition in exon 23 of the DST gene, resulting in a gln1124-to-ter (Q1124X) substitution in the coiled-coil domain. The mutation was not found in 200 ethnically matched chromosomes. RT-PCR showed 25% decreased gene expression in the 3-prime untranslated region with only slight reduction in expression for other gene regions. The coiled-coil domain is exclusively expressed in the BPAG1-e and BPAG1-n isoforms, which are expressed in the skin and nervous system, respectively. The patient had a lifelong history of trauma-induced spontaneous blisters and erosions particularly affecting his ankles and feet, although the face, trunk, and more proximal limbs were also affected. He also had nail dystrophy and moderate dental caries, but hair was normal and there was no history of mucosal blistering. Electron microscopic analysis of a skin biopsy showed discrete abnormalities of hemidesmosomes, with poorly formed inner plaques leading to a lucent zone between keratin filaments and outer hemidesmosomal plaques, which showed no gross abnormalities. Immunofluorescence staining showed absence of BPAG1-e at the dermal-epidermal junction and in keratinocytes. There was also decreased immunoreactivity for integrin beta-4 (ITGB4; 147557), PLEC1 (601282), and COL17A1 (113811). In 2 Israeli sisters of Iraqi descent (family A) with EBS with acral blistering, Ganani et al. (2021) identified homozygosity for a c.3370C-T transition in the DST gene (GRCh37), resulting in the previously reported Q1124X substitution. Neither sister displayed any neurologic symptoms. Their father and paternal grandmother were also affected; familial segregation was not reported. (less)
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Uncertain significance
(Mar 28, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539035.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with epidermolysis bullosa simplex or hereditary sensory and autonomic neuropathy type VI - characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities. However, this variant is in the penultimate exon of one DST transcript and was identified in this individual's mother in the homozygous state. The proband is het for this variant.- Not consistant with phenotype and genereviews says 100% penetrance HMS (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Jan 06, 2016)
|
Flagged submission
flagged submission
Method: literature only
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Hereditary sensory and autonomic neuropathy type 6
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174789.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln1124*) in the DST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DST are known to be pathogenic (PMID: 22522446, 25059916, 30371979). This variant is present in population databases (rs201045495, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with epidermolysis bullosa simplex (PMID: 20164846, 25059916). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66012). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with epidermolysis bullosa simplex or hereditary sensory and autonomic neuropathy type VI - characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities. However, this variant is in the penultimate exon of one DST transcript and was identified in this individual's mother in the homozygous state. The proband is het for this variant.- Not consistant with phenotype and genereviews says 100% penetrance HMS
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:
Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 27884173, 34426522, 30011071, 33471381, 35276021, 37431644, 37883475, 32802955, 37692655, 25059916, 20164846)
Comment:
This sequence change creates a premature translational stop signal (p.Gln1124*) in the DST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DST are known to be pathogenic (PMID: 22522446, 25059916, 30371979). This variant is present in population databases (rs201045495, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with epidermolysis bullosa simplex (PMID: 20164846, 25059916). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66012). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with epidermolysis bullosa simplex or hereditary sensory and autonomic neuropathy type VI - characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities. However, this variant is in the penultimate exon of one DST transcript and was identified in this individual's mother in the homozygous state. The proband is het for this variant.- Not consistant with phenotype and genereviews says 100% penetrance HMS
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Epidermolysis bullosa simplex due to bi-allelic DST mutations: Case series and review of the literature. | Ganani D | Pediatric dermatology | 2021 | PMID: 33471381 |
| Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI. | Fortugno P | Human mutation | 2019 | PMID: 30371979 |
| Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait. | Takeichi T | The British journal of dermatology | 2015 | PMID: 25059916 |
| Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. | Edvardson S | Annals of neurology | 2012 | PMID: 22522446 |
| A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. | Groves RW | The Journal of investigative dermatology | 2010 | PMID: 20164846 |
Text-mined citations for rs201045495 ...
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 Nov 25, 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.