ClinVar Genomic variation as it relates to human health
NM_015065.3(EXPH5):c.5422C>T (p.Arg1808Ter)
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.
Pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015065.3(EXPH5):c.5422C>T (p.Arg1808Ter)
Variation ID: 1805039 Accession: VCV001805039.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108510085 (GRCh38) [ NCBI UCSC ] 11: 108380812 (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 Dec 24, 2022 Feb 14, 2024 Feb 10, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015065.3:c.5422C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055880.2:p.Arg1808Ter nonsense NM_001144763.2:c.5194C>T NP_001138235.1:p.Arg1732Ter nonsense NM_001144764.2:c.4954C>T NP_001138236.1:p.Arg1652Ter nonsense NM_001144765.2:c.4858C>T NP_001138237.1:p.Arg1620Ter nonsense NM_001308019.2:c.5401C>T NP_001294948.1:p.Arg1801Ter nonsense NC_000011.10:g.108510085G>A NC_000011.9:g.108380812G>A NG_042852.2:g.102451C>T - Protein change
- R1620*, R1652*, R1732*, R1801*, R1808*
- Other names
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- Canonical SPDI
- NC_000011.10:108510084: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
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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
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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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EXPH5 | - | - |
GRCh38 GRCh37 |
232 | 255 |
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
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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 (1) |
criteria provided, single submitter
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May 6, 2021 | RCV002471457.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 10, 2022 | RCV002573607.2 |
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
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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
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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
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768126.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a reported mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a reported mechanism of disease in this gene and is associated with autosomal recessive nonspecific epidermolysis bullosa (MIM#615028; PMID: 27730671). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other variants predicted to result in a truncated protein comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two truncations downstream have been reported. p.(Pro1929Leufs*8) has been found in two families with recessive epidermolysis bullosa (PMIDs: 23176819, 32176379) and is also reported pathogenic in ClinVar, and p.(Phe1897Serfs*2) has been reported in an individual with fragile skin among other features such as intellectual disability (LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an individual. It was identified in a consanguineous family, in a homozygous individual who was also homozygous for p.(Thr68LeufsTer106) in the COL17A1 gene and presented with a complex blended phenotype (EB simplex and junctional EB) explained by both genes (PMID: 30016581). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Immunofluorescence staining showed no Exph5 protein in skin, however, the antibodies used were targeting the C-terminal, which is expected to be deleted in this truncated protein that is not predicted to result in nonsense mediated decay (PMID: 30016581). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Feb 10, 2022)
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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: SCV003292401.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1808*) in the EXPH5 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg1808*) in the EXPH5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the EXPH5 protein. This variant is present in population databases (rs142805294, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of EXPH5-related conditions (PMID: 28830826). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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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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Autosomal recessive epidermolysis bullosa simplex due to EXPH5 mutation: neonatal diagnosis of the first Italian case and literature review. | Diociaiuti A | Journal of the European Academy of Dermatology and Venereology : JEADV | 2020 | PMID: 32176379 |
Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1) in a patient with concomitant simplex and junctional epidermolysis bullosa. | Vahidnezhad H | Human mutation | 2018 | PMID: 30016581 |
Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications. | Vahidnezhad H | The Journal of investigative dermatology | 2017 | PMID: 28830826 |
A novel homozygous deletion in EXPH5 causes a skin fragility phenotype. | Malchin N | Clinical and experimental dermatology | 2016 | PMID: 27730671 |
Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility. | McGrath JA | American journal of human genetics | 2012 | PMID: 23176819 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 14, 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.