ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.294dup (p.Leu99fs) (rs776913277)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000372314 SCV000329114 pathogenic not provided 2018-04-02 criteria provided, single submitter clinical testing The c.294dupA variant in the BRAT1 gene has been reported in the compound heterozygous state with a second BRAT1 variant in two patients with a BRAT1-related disorder (Mundy et al., 2015; Hanes et al., 2015). The c.294dupA variant causes a frameshift starting with codon Leucine 99, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 92 of the new reading frame, denoted p.Leu99ThrfsX92. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.294dupA variant is observed in 20/14868 (0.135%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). We interpret c.294dupA as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000500824 SCV000593656 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2016-01-14 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000372314 SCV000610742 pathogenic not provided 2017-06-15 criteria provided, single submitter clinical testing
Invitae RCV000500824 SCV000652262 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2020-10-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu99Thrfs*92) in the BRAT1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs776913277, ExAC 0.1%). This variant has been reported in trans with a second rare BRAT1 variant in an individual affected with neonatal onset of hypertonia and seizures (PMID: 26494257) and in an individual affected with progressive global developmental delay, visual impairment, microcephaly, hypertonia, hyperreflexia, and seizures (PMID: 26483087). ClinVar contains an entry for this variant (Variation ID: 279703). Loss-of-function variants in BRAT1 are known to be pathogenic (PMID: 25500575, 27282546). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000372314 SCV000858548 pathogenic not provided 2017-12-05 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000500824 SCV000966182 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2018-07-10 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000500824 SCV000996133 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2018-04-20 criteria provided, single submitter clinical testing This frameshifting variant is predicted to result in a premature stop codon and is therefore considered a loss-of-function mutation. This variant has been previously reported as a compound heterozygous change in individuals with neurodevelopmental phenotypes of variable severity (PMID: 26494257, 26483087). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.023%. Based on the available evidence, the c.294dupA (p.Leu99ThrfsTer92) variant is classified as a pathogenic change.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000372314 SCV001449852 likely pathogenic not provided 2016-12-28 criteria provided, single submitter clinical testing
OMIM RCV000677129 SCV000803199 pathogenic Neurodevelopmental disorder with cerebellar atrophy and with or without seizures 2018-08-02 no assertion criteria provided literature only

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