ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.1163C>T (p.Ala388Val)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001299232 SCV001488315 uncertain significance Rigidity and multifocal seizure syndrome, lethal neonatal 2020-07-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 388 of the BRAT1 protein (p.Ala388Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs368710298, ExAC no frequency). This variant has not been reported in the literature in individuals with BRAT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001251686 SCV001427426 likely benign Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
GeneDx RCV001564796 SCV001788014 uncertain significance not provided 2020-06-11 no assertion criteria provided clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge

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