Submissions for variant NM_152743.4(BRAT1):c.283-2A>T

gnomAD frequency: 0.00006  dbSNP: rs147005619

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000805631	SCV000945594	likely pathogenic	Neonatal-onset encephalopathy with rigidity and seizures	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the BRAT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRAT1 are known to be pathogenic (PMID: 22279524, 25500575). This variant is present in population databases (rs147005619, gnomAD 0.05%). Disruption of this splice site has been observed in individual(s) with epilepsy (PMID: 31440721). ClinVar contains an entry for this variant (Variation ID: 650471). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272363	SCV002557308	uncertain significance	Neurodevelopmental disorder	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with BRAT1-related neurodevelopmental disorder. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (25 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice region, is present in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely pathogenic (ClinVar) and as a VUS (LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002537207	SCV003719764	likely pathogenic	Inborn genetic diseases	2021-01-06	criteria provided, single submitter	clinical testing	The c.283-2A>T intronic variant results from an A to T substitution two nucleotides before exon 4 (coding exon 3) of the BRAT1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx	RCV003318641	SCV004022617	likely pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing	Reported as a single heterozygous variant in an individual with epilepsy in published literature (Truty et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31440721)