ClinVar Genomic variation as it relates to human health
NM_153682.3(PIGP):c.384del (p.Glu129fs)
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_153682.3(PIGP):c.384del (p.Glu129fs)
Variation ID: 397552 Accession: VCV000397552.17
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 21q22.13 21: 37065603 (GRCh38) [ NCBI UCSC ] 21: 38437903 (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 Mar 27, 2017 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153682.3:c.384del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_710149.1:p.Glu129fs frameshift NM_001320480.2:c.384del NP_001307409.1:p.Glu129fs frameshift NM_016430.4:c.306del NP_057514.2:p.Glu103fs frameshift NM_153681.2:c.456del NP_710148.1:p.Glu153fs frameshift NM_153681.2:c.456delA NC_000021.9:g.37065605del NC_000021.8:g.38437905del - Protein change
- E103fs, E129fs, E153fs
- Other names
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- Canonical SPDI
- NC_000021.9:37065602:TTT:TT
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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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PIGP | - | - |
GRCh38 GRCh37 |
116 | 211 |
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
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
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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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Uncertain significance (1) |
no assertion criteria provided
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Feb 23, 2017 | RCV000449561.2 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2022 | RCV000496365.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV001543513.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Oct 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 55
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150211.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762128.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Seizure (present) , Global developmental delay (present) , Absent speech (present)
Sex: male
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Pathogenic
(Aug 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 55
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002567983.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Comment:
The c.384del;p.(Glu129Asnfs*34) is a null frameshift variant (NMD) in the PIGP gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD); it is … (more)
The c.384del;p.(Glu129Asnfs*34) is a null frameshift variant (NMD) in the PIGP gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD); it is present in a relevant exon to the transcript, and disrupts < 10% of the protein product – PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: ID: 397552; OMIM: 605938.0002; PMID: 32042915; 31139695; 28334793) - PS4. The variant is present at low allele frequencies population databases (rs778481061 – gnomAD 0.0003944%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(Glu129Asnfs*34) was detected in trans with a pathogenic variant (PMID: 32042915; 31139695; 28334793) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32042915) - PP1_moderate. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Argentina
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Likely pathogenic
(Jan 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 55
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024631.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 27, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002246996.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change results in a frameshift in the PIGP gene (p.Glu153Asnfs*34). While this is not anticipated to result in nonsense mediated decay, it is … (more)
This sequence change results in a frameshift in the PIGP gene (p.Glu153Asnfs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the PIGP protein and extend the protein by 27 additional amino acid residues. This variant is present in population databases (rs778481061, gnomAD 0.007%). This frameshift has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 28334793, 31139695, 32042915). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.384del. ClinVar contains an entry for this variant (Variation ID: 397552). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects PIGP function (PMID: 28334793). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Feb 23, 2017)
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no assertion criteria provided
Method: research
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Early Infantile Epileptic Encephalopathy
Affected status: yes
Allele origin:
paternal
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Care4Rare-SOLVE, CHEO
Study: Care4Rare
Accession: SCV000537759.1 First in ClinVar: Mar 27, 2017 Last updated: Mar 27, 2017 |
Comment:
This variant was found in a compound heterozygous state with c.74T>C.
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Nov 11, 2020)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 55
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000586814.5
First in ClinVar: Aug 07, 2017 Last updated: Nov 14, 2020 |
Comment on evidence:
For discussion of the 1-bp deletion (c.456delA, NM_153681.2) in the PIGP gene, resulting in a frameshift and premature termination (Glu153AsnfsTer34), that was found in compound … (more)
For discussion of the 1-bp deletion (c.456delA, NM_153681.2) in the PIGP gene, resulting in a frameshift and premature termination (Glu153AsnfsTer34), that was found in compound heterozygous state in 2 sibs with developmental and epileptic encephalopathy-55 (DEE55; 617599) by Johnstone et al. (2017), see 605938.0001. In a 2-year-old girl, born of unrelated Polish parents, with DEE55, Krenn et al. (2019) identified homozygosity for the c.456delA mutation in the PIGP gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at low frequencies in only heterozygous state in an in-house database (6 in over 16,000 exomes) and gnomAD (9 exomes). Flow cytometric analysis of patient lymphocytes showed decreased expression of GPI-anchored proteins, suggesting a loss-of-function effect. The findings confirmed PIGP as a monogenic disease causing developmental and epileptic encephalopathy. The patient had onset of refractory focal seizures at 7 months of age. Developmental milestones were not reached. In 4 affected individuals from a large consanguineous kindred with DEE55, Vetro et al. (2020) identified a homozygous 1-bp deletion (c.384del, NM_153682.2) in the PIGP gene, predicted to result in a frameshift and premature termination (Glu129AsnfsTer34). The authors stated that this was the same mutation as that reported by Krenn et al. (2019). The mutation identified by Vetro et al. (2020) was found by exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder in the family and was found at a low frequency in the gnomAD database (3 x 10(-5)). Flow cytometric analysis of patient lymphocytes showed decreased levels of the GPI-anchored protein CD16 (146740) and mildly decreased levels of CD24 (600074), whereas expression of another GPI-anchored protein, CD55 (125240), was normal. The patients had onset of refractory focal and generalized seizures at 3 months of age. EEG showed burst-suppression pattern. The patients achieved almost no developmental milestones; 2 died at 12 years and 27 months, respectively. (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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Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations. | Vetro A | Neurology. Genetics | 2020 | PMID: 32042915 |
Biallelic mutations in PIGP cause developmental and epileptic encephalopathy. | Krenn M | Annals of clinical and translational neurology | 2019 | PMID: 31139695 |
Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. | Johnstone DL | Human molecular genetics | 2017 | PMID: 28334793 |
Text-mined citations for rs778481061 ...
HelpRecord 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.