Submissions for variant NM_152743.4(BRAT1):c.826G>A (p.Asp276Asn)

gnomAD frequency: 0.00070  dbSNP: rs146546197

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000552115	SCV000652279	likely benign	Neonatal-onset encephalopathy with rigidity and seizures	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001565940	SCV001789389	uncertain significance	not provided	2022-08-26	criteria provided, single submitter	clinical testing	Observed in individual with ataxia, spastic paraparesis, leukodystrophy and cognitive decline who also harbored a second BRAT1 variant in the compound heterozygous state; however, this individual also harbored a homozygous variant in the PEX16 gene which was considered by the authors to be disease causative (Bacino et. al., 2016).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26870756)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000552115	SCV002768449	uncertain significance	Neonatal-onset encephalopathy with rigidity and seizures	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS - 3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine (exon 6). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (P) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals. This variant has been reported once a likely benign (ClinVar). This variant was also observed in a patient with atypical peroxisomal biogenesis disorder, but an alternative diagnosis in PEX6 was found (PMID: 26870756). (B) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Ambry Genetics	RCV002530202	SCV003562493	likely benign	Inborn genetic diseases	2021-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV003952840	SCV004771285	likely benign	BRAT1-related condition	2022-07-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).