ClinVar Genomic variation as it relates to human health
NM_153682.3(PIGP):c.2T>C (p.Met1Thr)
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.2T>C (p.Met1Thr)
Variation ID: 397551 Accession: VCV000397551.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.13 21: 37072514 (GRCh38) [ NCBI UCSC ] 21: 38444814 (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 Sep 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153682.3:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_710149.1:p.Met1Thr missense initiator codon variant NM_001320480.2:c.2T>C NP_001307409.1:p.Met1Thr missense initiator codon variant NM_016430.4:c.-243T>C 5 prime UTR NM_153681.2:c.74T>C NP_710148.1:p.Met25Thr missense NM_153682.2:c.2T>C NC_000021.9:g.37072514A>G NC_000021.8:g.38444814A>G - Protein change
- M25T, M1T
- Other names
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- Canonical SPDI
- NC_000021.9:37072513:A:G
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00007
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
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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PIGP | - | - |
GRCh38 GRCh37 |
115 | 208 |
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
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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 | RCV000449500.2 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2022 | RCV000496825.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 15, 2023 | RCV001851116.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2020 | RCV002252129.2 |
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
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
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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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Likely pathogenic
(May 28, 2019)
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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:
unknown
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Mendelics
Accession: SCV001141295.2
First in ClinVar: Jan 13, 2020 Last updated: Sep 03, 2023 |
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Likely pathogenic
(Feb 14, 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: SCV002097278.2
First in ClinVar: Feb 20, 2022 Last updated: Sep 03, 2023 |
Comment:
The c.2T>C;p.(Met1?) is a start-loss variant in the PIGP gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon … (more)
The c.2T>C;p.(Met1?) is a start-loss variant in the PIGP gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28334793) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 397551; PMID: 28334793; 32042915; 31139695) - PS4. The variant is present at low allele frequencies population databases (rs768633670 - gnomAD 0.0003943%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Met1?) was detected in trans with a pathogenic variant (PMID: 28334793; 32042915) - PM3. In summary, the currently available evidence indicates that the variant is likely pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Likely pathogenic
(Nov 23, 2021)
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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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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512697.2
First in ClinVar: May 21, 2022 Last updated: Sep 03, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderate, PM3 moderate, PP1 supporting
Geographic origin: Brazil
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Likely pathogenic
(Mar 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523602.2
First in ClinVar: Jun 09, 2022 Last updated: Sep 03, 2023 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3
Clinical Features:
Seizure (present) , Neurodevelopmental abnormality (present)
Geographic origin: Brazil
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Pathogenic
(Sep 15, 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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Invitae
Accession: SCV002242159.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the PIGP protein (p.Met25Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the PIGP protein (p.Met25Thr). This variant is present in population databases (rs768633670, gnomAD 0.006%). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 28334793). 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. ClinVar contains an entry for this variant (Variation ID: 397551). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change 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:
maternal
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Care4Rare-SOLVE, CHEO
Study: Care4Rare
Accession: SCV000537758.2 First in ClinVar: Mar 27, 2017 Last updated: Sep 03, 2023 |
Comment:
This variant was found in a compound heterozygous state with c.456delA.
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: SCV000586813.5
First in ClinVar: Aug 07, 2017 Last updated: Sep 03, 2023 |
Comment on evidence:
In 2 sibs with developmental and epileptic encephalopathy-55 (DEE55; 617599), Johnstone et al. (2017) identified compound heterozygous mutations in the PIGP gene: a c.74T-C transition … (more)
In 2 sibs with developmental and epileptic encephalopathy-55 (DEE55; 617599), Johnstone et al. (2017) identified compound heterozygous mutations in the PIGP gene: a c.74T-C transition (c.74T-C, NM_153681.2), resulting in a met25-to-thr (M25T) substitution at a highly conserved residue, and a 1-bp deletion (c.456delA; 605938.0002) in the final exon, resulting in a frameshift and premature termination (Glu153AsnfsTer34). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The M25T variant occurs in isoform 1; in isoform 2 (NM_153682.2), this variant leads to a loss of the start codon. The variants were filtered against the 1000 Genomes Project, Exome Variant Server, and ExAC databases. The M25T variant was found at a very low frequency (2.47 x 10(-5)) in the ExAC database. Patient fibroblasts showed decreased PIGP mRNA and presumably decreased protein levels, as well as decreased cell surface expression of GPI-anchored proteins; this defect could be rescued by overexpression of PIGP isoform 2. Transfection of the mutations into PIGP-deficient cells was also associated with decreased expression of GPI-anchored proteins. The patients had onset of refractory focal seizures in the first weeks of life. They had profound developmental delay. One sib died at 26 months of age. (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 rs768633670 ...
HelpRecord last updated Feb 20, 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.