ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.1825C>T (p.Arg609Trp) (rs886039312)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255518 SCV000321419 likely pathogenic not provided 2016-01-04 criteria provided, single submitter clinical testing The R609W variant in the BRAT1 gene has now been reported by Hanes et al. (2015) in a child with lethal neonatal rigidity and seizure syndrome and the c.294dupA variant on the opposite BRAT1 allele, who is likely this individual's niece. The R609W variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R609W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R609W variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000650104 SCV000771941 uncertain significance Rigidity and multifocal seizure syndrome, lethal neonatal 2017-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 609 of the BRAT1 protein (p.Arg609Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with lethal neonatal rigidity and multifocal seizure syndrome (PMID: 26483087). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 265048). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
OMIM RCV000677128 SCV000803198 pathogenic Neurodevelopmental disorder with cerebellar atrophy and with or without seizures 2018-08-02 no assertion criteria provided literature only

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