ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.1340C>T (p.Thr447Met) (rs368808380)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658358 SCV000780130 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing The T447M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T447M variant is observed in 8/22330 (0.04%) alleles from individuals of Latino background (Lek et al., 2016). The T447M 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000810816 SCV000951051 uncertain significance Rigidity and multifocal seizure syndrome, lethal neonatal 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 447 of the BRAT1 protein (p.Thr447Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs368808380, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRAT1-related disease. 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 methionine 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. 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.
Baylor Genetics RCV000810816 SCV001525447 uncertain significance Rigidity and multifocal seizure syndrome, lethal neonatal 2019-10-24 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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