rs1554616628
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_012479.4(YWHAG):c.394C>T(p.Arg132Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_012479.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
YWHAG | NM_012479.4 | c.394C>T | p.Arg132Cys | missense_variant | 2/2 | ENST00000307630.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
YWHAG | ENST00000307630.5 | c.394C>T | p.Arg132Cys | missense_variant | 2/2 | 1 | NM_012479.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 56 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 10, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 03, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | May 06, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Apr 16, 2018 | 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). - |
Pathogenic, no assertion criteria provided | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics laboratory, Necker Hospital | Mar 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2023 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | 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. - |
YWHAG-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 28, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at