Submissions for variant NM_012479.4(YWHAG):c.169C>T (p.Arg57Cys)

dbSNP: rs1583981736

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816037	SCV000956525	pathogenic	not provided	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 57 of the YWHAG protein (p.Arg57Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy or its clinical features (PMID: 31926053; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 659092). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt YWHAG protein function with a positive predictive value of 80%. This variant disrupts the p.Arg57 amino acid residue in YWHAG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31926053). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000816037	SCV001874114	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33726816, 34580403, 35982160, 33393734, 31926053)
Illumina Laboratory Services, Illumina	RCV001788360	SCV002034854	pathogenic	Developmental and epileptic encephalopathy, 56	2021-07-30	criteria provided, single submitter	clinical testing	The YWHAG c.169C>T (p.Arg57Cys) variant is a missense variant that has been reported in a confirmed de novo heterozygous state in one individual with developmental and epileptic encephalopathy (Kanani et al. 2019). Clinical features in this individual include seizures, global developmental delays, speech delays, and moderate intellectual disability. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequence coverage, which suggests the variant is rare. Kanani et al. (2019) identified a second individual who carried another de novo heterozygous variant at the same nucleotide position that results in a different amino acid change, c.169C>G (p.Arg57Gly); this variant is also absent from versions 2.1.1 and 3.1.1 of the Genome Aggregation Database. The Arg57 residue is part of the highly conserved triad of Arg-132, Arg-57, and Tyr-133, which is part of the protein binding groove and is responsible for fixing the orientation of phosphopeptides (Kanani et al. 2019). Multiple predictive algorithms suggest the p.Arg57Cys variant to be damaging to the protein, though these predictions have not been experimentally confirmed. Based on the available evidence, the p.Arg57Cys variant is classified as pathogenic for YWHAG-related developmental and epileptic encephalopathy.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002267626	SCV002549838	pathogenic	Seizure; Failure to thrive; Constipation; Spasticity; Microcephaly; Intellectual disability; Severe global developmental delay; Hypotonia	2022-06-23	criteria provided, single submitter	clinical testing	This variant was found as mosaic. This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PM5_STR, PS2_MOD, PS4_MOD, PM2_SUP, PP3
Ambry Genetics	RCV004962845	SCV005534605	pathogenic	Inborn genetic diseases	2024-10-29	criteria provided, single submitter	clinical testing	The c.169C>T (p.R57C) alteration is located in exon 2 (coding exon 2) of the YWHAG gene. This alteration results from a C to T substitution at nucleotide position 169, causing the arginine (R) at amino acid position 57 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with epilepsy, global developmental delay, intellectual disability, speech delay, and/or dysmorphic facial features (Kanani, 2020; Pode-Shakked, 2021; Ko, 2023). Another alteration at the same codon, c.170G>A (p.R57H), has been detected de novo in multiple individuals with clinical features consistent with YWHAG-related developmental and epileptic encephalopathy (Sedláková, 2021; Yi, 2022; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Pediatric Genetics Clinic, Sheba Medical Center	RCV001788360	SCV001712254	pathogenic	Developmental and epileptic encephalopathy, 56	2021-05-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892747	SCV004709807	pathogenic	YWHAG-related disorder	2024-07-29	no assertion criteria provided	clinical testing	The YWHAG c.169C>T variant is predicted to result in the amino acid substitution p.Arg57Cys. This variant was reported de novo in two children with clinical features YWHAG-related disease (Kanani et al. 2020. PubMed ID: 31926053; Internal Data, PreventionGenetics). It has also been reported de novo in children with developmental and epileptic encephalopathy (Pode-Shakked et al. 2021. PubMed ID: 34580403; Certica et al. 2024. PubMed ID: 38491959) and myoclonic atonic encephalopathy (Table S1, Certica et al. 2024. PubMed ID: 38491959). Alternate nucleotide changes affecting the same amino acid (p.Arg57Gly; p.Arg57His) have been reported in individuals with YWHAG-related disorders (Kanani et al. 2020. PubMed ID: 31926053; Table S1 and S2, Certica et al. 2024. PubMed ID: 38491959). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by multiple submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/659092/). This variant is interpreted as pathogenic.