Submissions for variant NM_012479.4(YWHAG):c.395G>A (p.Arg132His)

dbSNP: rs1583981615

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995916	SCV001150314	pathogenic	Developmental and epileptic encephalopathy, 56	2018-05-04	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001171618	SCV001334416	pathogenic	not provided	2019-11-06	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000995916	SCV002557769	pathogenic	Developmental and epileptic encephalopathy, 56	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, computational modelling has suggested loss-of-function is the mechanism of disease (PMID: 33767733). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. (PMID: 33767733). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg132Cys) variant has been shown to be de novo in at least two individuals and classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 31926053). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported once as a de novo event and classified as pathogenic by diagnostic laboratories in ClinVar . (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV001171618	SCV003029511	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 132 of the YWHAG protein (p.Arg132His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile epileptic encephalopathy (PMID: 33619735). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 807723). 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%. This variant disrupts the p.Arg132 amino acid residue in YWHAG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28777935, 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.
Revvity Omics, Revvity	RCV000995916	SCV003823843	uncertain significance	Developmental and epileptic encephalopathy, 56	2021-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001171618	SCV005626618	pathogenic	not provided	2024-07-13	criteria provided, single submitter	clinical testing	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: 33619735)