ClinVar Genomic variation as it relates to human health
NM_012479.4(YWHAG):c.394C>T (p.Arg132Cys)
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_012479.4(YWHAG):c.394C>T (p.Arg132Cys)
Variation ID: 438804 Accession: VCV000438804.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.23 7: 76329927 (GRCh38) [ NCBI UCSC ] 7: 75959244 (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 Sep 28, 2017 Feb 14, 2024 Dec 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012479.4:c.394C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036611.2:p.Arg132Cys missense NC_000007.14:g.76329927G>A NC_000007.13:g.75959244G>A - Protein change
- R132C
- Other names
- NM_012479.3:c.394C>T(p.Arg132Cys)
- Canonical SPDI
- NC_000007.14:76329926: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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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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YWHAG | - | - |
GRCh38 GRCh37 |
181 | 220 |
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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2019 | RCV000505695.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2023 | RCV001591150.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2023 | RCV003392338.4 |
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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Likely pathogenic
(Apr 16, 2018)
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criteria provided, single submitter
Method: curation
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Developmental and epileptic encephalopathy, 56
Affected status: unknown
Allele origin:
germline
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SIB Swiss Institute of Bioinformatics
Accession: SCV000787485.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
Comment:
This variant is interpreted as a Likely Pathogenic, for Epileptic encephalopathy, early infantile, 56, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PP3 => … (more)
This variant is interpreted as a Likely Pathogenic, for Epileptic encephalopathy, early infantile, 56, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28777935). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:28777935). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PMID:28777935) (http://www.uniprot.org/uniprot/P61981#showFeaturesTable). (less)
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 56
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439898.2
First in ClinVar: Oct 31, 2020 Last updated: Dec 07, 2020 |
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Pathogenic
(Dec 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 56
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001519842.1
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
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001824058.2
First in ClinVar: Sep 08, 2021 Last updated: Jun 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33767733, 28777935, 28135719, 31164858, 33393734, 31926053, 33349918, 32725632, 31785789, 36243722, 35888005, 34915349, 33619735) (less)
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Pathogenic
(Feb 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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YWHAG-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004112046.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The YWHAG c.394C>T variant is predicted to result in the amino acid substitution p.Arg132Cys. This variant has been documented as a recurrent de novo variant … (more)
The YWHAG c.394C>T variant is predicted to result in the amino acid substitution p.Arg132Cys. This variant has been documented as a recurrent de novo variant in multiple individuals with early onset epileptic encephalopathy (See for example - Guella et al. 2017. PubMed ID: 28777935; Demos et al. 2019. PubMed ID: 31164858; Kanani et al. 2020. PubMed ID: 31926053). Additionally, a different missense variant affecting this amino acid (p.Arg132His) has been documented to be pathogenic (Brunet et al. 2021. PubMed ID: 33619735). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Dec 22, 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: SCV002236694.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the YWHAG protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the YWHAG protein (p.Arg132Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of YWHAG-related conditions (PMID: 28777935, 31926053). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 438804). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt YWHAG protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 03, 2020)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 56
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000599981.3
First in ClinVar: Sep 28, 2017 Last updated: Dec 07, 2020 |
Comment on evidence:
In 3 unrelated females (subjects B, E, and F) with developmental and epileptic encephalopathy-56 (DEE56; 617665), Guella et al. (2017) identified a de novo heterozygous … (more)
In 3 unrelated females (subjects B, E, and F) with developmental and epileptic encephalopathy-56 (DEE56; 617665), Guella et al. (2017) identified a de novo heterozygous c.394C-T transition (c.394C-T, NM_012479.3) in the YWHAG gene, resulting in an arg132-to-cys (R132C) substitution at a highly conserved residue in a conserved triad of 2 arginines and a tyrosine that form a positively charged pocket within a binding groove for interacting phosphopeptides. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional studies of the variant and studies of patient cells were not performed. The patients had onset of seizures in the first months or years of life. (less)
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Pathogenic
(May 06, 2020)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 56
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469184.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 56
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001547550.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Sex: female
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Pathogenic
(Mar 02, 2022)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
de novo
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Molecular Genetics laboratory, Necker Hospital
Accession: SCV004031297.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Clinical Features:
Intellectual disability (present)
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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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Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy. | Kanani F | American journal of medical genetics. Part A | 2020 | PMID: 31926053 |
De Novo Mutations in YWHAG Cause Early-Onset Epilepsy. | Guella I | American journal of human genetics | 2017 | PMID: 28777935 |
Text-mined citations for rs1554616628 ...
HelpRecord last updated Mar 11, 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.