Submissions for variant NM_152743.4(BRAT1):c.393_422dup (p.Gln132_Ala141dup)

dbSNP: rs1562582216

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000823282	SCV000964133	uncertain significance	Neonatal-onset encephalopathy with rigidity and seizures	2018-11-26	criteria provided, single submitter	clinical testing	This variant, c.393_422dup, results in the insertion of 10 amino acid(s) to the BRAT1 protein (p.Gln132_Ala141dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRAT1-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Hadassah Hebrew University Medical Center	RCV000823282	SCV001736915	pathogenic	Neonatal-onset encephalopathy with rigidity and seizures	2019-06-20	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223958	SCV002502169	uncertain significance	not provided	2022-03-03	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002227498	SCV002507057	uncertain significance	Neurodevelopmental disorder with cerebellar atrophy and with or without seizures	2022-05-04	criteria provided, single submitter	curation	The homozygous p.Gln132_Ala141dup variant in BRAT1 was identified by our study in 1 individual with neurodevelopmental disorder with cerebellar atrophy with or without seizures. The variant has not been previously reported in individuals with neurodevelopmental disorder with cerebellar atrophy with or without seizures and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 665075) as having uncertain significance by Invitae. This variant is an insertion of 30 bases at position 393 and is not predicted to alter the protein reading-frame. It is unclear if this insertion will impact the protein. In summary, the clinical significance of the p.Gln132_Ala141dup variant is uncertain. ACMG/AMP Criteria applied: PM4, PM2, PM3_supporting (Richards 2015).