ClinVar Genomic variation as it relates to human health
NM_004855.5(PIGB):c.847-10A>G
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
-
NM_004855.5(PIGB):c.847-10A>G
Variation ID: 689519 Accession: VCV000689519.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q21.3 15: 55340602 (GRCh38) [ NCBI UCSC ] 15: 55632800 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 16, 2019 Feb 20, 2024 Jan 7, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004855.5:c.847-10A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000015.10:g.55340602A>G NC_000015.9:g.55632800A>G - Protein change
- Other names
- IVS7AS, A-G, -10
- Canonical SPDI
- NC_000015.10:55340601:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00016
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. |
|||
PIGB | - | - |
GRCh38 GRCh37 |
271 | 349 |
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 (1) |
criteria provided, single submitter
|
Jan 7, 2024 | RCV002538350.2 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2023 | RCV000850267.7 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 80
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557027.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The PIGB c.847-10A>G variant is classified as PATHOGENIC (PS4, PVS1) The PIGB c.847-10A>G is a single nucleotide change located in intron 7 of the gene. … (more)
The PIGB c.847-10A>G variant is classified as PATHOGENIC (PS4, PVS1) The PIGB c.847-10A>G is a single nucleotide change located in intron 7 of the gene. Studies have demonstrated that this variant introduces a new acceptor site and results in no wild-type mRNA being expressed (PMID:31256876). This variant has been previously reported in a homozygous state in affected individuals from multiple families with glycosylphosphatidylinositol deficiency (PMID:31256876) (PS4). This variant is in dbSNP (rs779296101) but is rare in population databases (gnomAD 1/152128 alleles). This variant has been reported in ClinVar as pathogenic for developmental and epileptic encephalopathy 80 by another diagnostic laboratory (Variation ID:689519). It is also reported as damaging in the disease database HGMD (CS1915182). (less)
|
|
Pathogenic
(Jul 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 80
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004041364.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 80
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV004046878.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
This homozygous intronic variant is identified in a 3 month male with poor feeding, coarse face, who later developed GDD hypertrichosis and raised alkaline phosphatase. … (more)
This homozygous intronic variant is identified in a 3 month male with poor feeding, coarse face, who later developed GDD hypertrichosis and raised alkaline phosphatase. Microanalysis: normal. Sibling died with a similar phenotype. This change present in gnomAD database with an allele frequency of 0.0065% [PM2]. To our knowledge there are no homozygotes in gnomAd database for this variant. Insilico prediction [SpliceAI, dbscSNV] predicts a splice-altering nature of this variant [PP3]. A clinvar entry [Variation ID: 689519] for this variant is available with a “Pathogenic” interpretation by multiple submitter. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic" (less)
|
|
Pathogenic
(Jan 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003474094.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 7 of the PIGB gene. It does not directly change the encoded amino acid sequence of the PIGB protein. … (more)
This sequence change falls in intron 7 of the PIGB gene. It does not directly change the encoded amino acid sequence of the PIGB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs779296101, gnomAD 0.05%). This variant has been observed in individual(s) with PIGB-related conditions (PMID: 31256876). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 689519). Studies have shown that this variant alters PIGB gene expression (PMID: 31256876, 32123317). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 31256876). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Oct 20, 2020)
|
no assertion criteria provided
Method: literature only
|
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000992439.2
First in ClinVar: Sep 16, 2019 Last updated: Oct 23, 2020 |
Comment on evidence:
In 6 patients from 4 unrelated families (4, 6, 7, and 10) with developmental and epileptic encephalopathy-80 (DEE80; 618580), Murakami et al. (2019) identified a … (more)
In 6 patients from 4 unrelated families (4, 6, 7, and 10) with developmental and epileptic encephalopathy-80 (DEE80; 618580), Murakami et al. (2019) identified a homozygous A-to-G transition in intron 7 of the PIGB gene (c.847-10A-G, NM_004855.4), resulting in the inclusion of 9 nucleotides of intron 7 in the mRNA and an abnormal splicing variant (Gln282_Trp283insArgCysGln). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. The variant was found at low frequencies in heterozygous state in the ExAC (0.0001592) and gnomAD (6.51 x 10(-5)) databases. Lymphocytes and fibroblasts derived from some patients showed decreased levels of cell surface GPI-anchored proteins, ranging from about 25 to 50% compared to controls. In vitro functional expression studies in PIGB-null CHO cells showed low levels of the mutant protein, suggesting that it is unstable, and partial restoration of GPI-AP surface proteins compared to wildtype. The age at onset of seizures in these patients was highly variable, ranging from the first days to about one year of life. (less)
|
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 |
---|---|---|---|---|
Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. | Wai HA | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32123317 |
Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases. | Murakami Y | American journal of human genetics | 2019 | PMID: 31256876 |
Text-mined citations for rs779296101 ...
HelpRecord last updated Feb 28, 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.