ClinVar Genomic variation as it relates to human health
NM_001127178.3(PIGG):c.1515G>A (p.Trp505Ter)
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(8); Likely pathogenic(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001127178.3(PIGG):c.1515G>A (p.Trp505Ter)
Variation ID: 476318 Accession: VCV000476318.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 515631 (GRCh37) [ NCBI UCSC ] 4: 521842 (GRCh38) [ 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 Feb 13, 2018 May 12, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127178.3:c.1515G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001120650.1:p.Trp505Ter nonsense NM_001289051.2:c.1248G>A NP_001275980.1:p.Trp416Ter nonsense NM_001289052.2:c.1116G>A NP_001275981.1:p.Trp372Ter nonsense NM_001289053.2:c.1248G>A NP_001275982.1:p.Trp416Ter nonsense NM_001289055.2:c.*77G>A 3 prime UTR NM_001289057.2:c.*130G>A 3 prime UTR NM_001345986.2:c.1248G>A NP_001332915.1:p.Trp416Ter nonsense NM_001345987.2:c.1224G>A NP_001332916.1:p.Trp408Ter nonsense NM_001345988.2:c.486G>A NP_001332917.1:p.Trp162Ter nonsense NM_001345989.2:c.1515G>A NP_001332918.1:p.Trp505Ter nonsense NM_001345990.2:c.-19G>A 5 prime UTR NM_001345991.2:c.-19G>A 5 prime UTR NM_001345994.2:c.417G>A NP_001332923.1:p.Trp139Ter nonsense NM_017733.5:c.1491G>A NP_060203.3:p.Trp497Ter nonsense NR_110293.2:n.1595G>A non-coding transcript variant NR_144326.2:n.1877G>A non-coding transcript variant NR_144327.2:n.1641G>A non-coding transcript variant NR_144328.2:n.1595G>A non-coding transcript variant NR_144329.2:n.1831G>A non-coding transcript variant NR_144330.2:n.1641G>A non-coding transcript variant NR_144331.2:n.1877G>A non-coding transcript variant NR_144332.2:n.1641G>A non-coding transcript variant NR_144333.2:n.1641G>A non-coding transcript variant NR_144334.2:n.1831G>A non-coding transcript variant NC_000004.12:g.521842G>A NC_000004.11:g.515631G>A NG_051621.1:g.27643G>A - Protein change
- W505*, W139*, W162*, W408*, W497*, W372*, W416*
- Other names
- -
- Canonical SPDI
- NC_000004.12:521841: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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00059
The Genome Aggregation Database (gnomAD), exomes 0.00066
Exome Aggregation Consortium (ExAC) 0.00072
The Genome Aggregation Database (gnomAD) 0.00073
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077
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 | ||
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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. |
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PIGG | - | - |
GRCh38 GRCh37 |
988 | 1158 |
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. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000547936.18 | |
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000579067.31 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 30, 2021 | RCV002526732.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2021 | RCV002506370.2 |
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
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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Pathogenic
(May 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000681244.6
First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023 |
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 … (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: 31414351, 31980526, 34113002, 26996948, 34535746, 33921431) (less)
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Pathogenic
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000656861.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp505*) in the PIGG gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp505*) in the PIGG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGG are known to be pathogenic (PMID: 26996948, 28581210, 28771251). This variant is present in population databases (rs150259543, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PIGG-related conditions. ClinVar contains an entry for this variant (Variation ID: 476318). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001525274.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558012.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 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 known 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 known mechanism of disease in this gene and is associated with autosomal recessive intellectual disability 53 (MIM#616917). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. This individual has a terminal 4p16.3 deletion encompassing the PIGG gene on the other allele. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (186 heterozygotes, 0 homozygotes), however there is 1 homozygote present in gnomAD v3. (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other variants predicted to result in a loss of function have previously been reported in individuals with autosomal recessive intellectual disability 53 (MIM#616917) (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in at least five individuals with autosomal recessive intellectual disability 53 (MIM#616917) (ClinVar). (SP) 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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Pathogenic
(Sep 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
BLOOD GROUP, EMM SYSTEM
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811533.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 13, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799192.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
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Likely pathogenic
(Oct 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799011.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PVS1, PM3
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598683.2
First in ClinVar: Nov 05, 2022 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PIGG c.1515G>A (p.Trp505X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more)
Variant summary: PIGG c.1515G>A (p.Trp505X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00066 in 251480 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. c.1515G>A has been reported in the literature in at least one homozygous individual affected with Autism Spectrum Disorder-Asperger type (Arteche-Lopez_2021). The variant was also found in another homozygous individual with seizures and mild clumsiness, although this second individual was too young to evaluate for intellectual disability (Trembley-Laganiere_2021). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=7), likely pathogenic (n=2), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Feb 08, 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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Revvity Omics, Revvity
Accession: SCV002024625.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely benign
(Jul 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003701329.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246490.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
PIGG: PVS1, PM3, PM2:Supporting
Number of individuals with the variant: 3
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551154.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034182.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037320.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037710.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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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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PIGG variant pathogenicity assessment reveals characteristic features within 19 families. | Tremblay-Laganière C | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34113002 |
Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test. | Arteche-López A | Genes | 2021 | PMID: 33921431 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. | Lionel AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28771251 |
Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function. | Zhao JJ | Human mutation | 2017 | PMID: 28581210 |
Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia. | Makrythanasis P | American journal of human genetics | 2016 | PMID: 26996948 |
Text-mined citations for rs150259543 ...
HelpRecord last updated May 12, 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.