ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.1925C>A (p.Ala642Glu) (rs200502048)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520398 SCV000618455 likely pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing The A642E variant in the BRAT1 gene has been reported previously in an individual with global developmental delays, microcephaly, hyperreflexia, and seizures who also harbored an additional disease-causing variant in the BRAT1 gene in trans (Mundy et al., 2016). This individual had a milder phenotype with longer survival and was six years old at the time the report was published (Mundy et al., 2016). The A642E variant is observed in 8/89,758 (0.009%) alleles from individuals of non-Finnish European background in the ExAC dataset, with no homozygous individuals reported (Lek et al., 2016). The A642E 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 not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A642E as a likely pathogenic variant.
Invitae RCV000534851 SCV000652246 uncertain significance Rigidity and multifocal seizure syndrome, lethal neonatal 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 642 of the BRAT1 protein (p.Ala642Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with clinical features of neonatal-lethal rigidity and multifocal seizure syndrome (PMID: 26494257. In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 RCV000677134 SCV000803204 pathogenic Neurodevelopmental disorder with cerebellar atrophy and with or without seizures 2018-08-02 no assertion criteria provided literature only

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