ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.638dup (p.Val214fs) (rs730880324)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210714 SCV000262862 pathogenic Inborn genetic diseases 2017-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000268435 SCV000329115 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing The c.638dupA variant in the BRAT1 gene has been reported previously, sometimes as c.638_639insA due to the use of alternative nomenclature, in the homozygous state in infants and children under 2 years of age with lethal neonatal rigidity and multifocal seizure syndrome (Puffenberger et al., 2012; van de Pol et al., 2015). The c.638dupA variant has also been reported in trans (on the opposite allele) with splice site and missense BRAT1 variants in unrelated children who had a milder phenotype with survival beyond 4 years of age (Srivastava et al., 2016; Fernández-Jaén et al., 2016). Variable expression has also been described in brothers who had the c.638dupA variant in trans with a splice site variant (Horn et al., 2016). The c.638dupA variant causes a frameshift starting with codon Valine 214, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 189 of the new reading frame, denoted p.Val214GlyfsX189. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and functional studies suggest that it causes protein destabilization and leads to aggregation of mutant BRAT1 protein in the cytoplasm (Puffenberger et al., 2012). The c.638dupA variant is observed in 33/64676 (0.05%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.638dupA as a pathogenic variant.
Invitae RCV000024198 SCV000652273 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2020-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val214Glyfs*189) in the BRAT1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730880324, ExAC 0.05%). This variant has been reported as homozygous in several individuals with lethal neonatal rigidity and seizure syndrome (PMID: 22279524, 26535877) and as compound heterozygous in individuals with varying clinical severity, including early-onset epileptic encephalopathy, progressive encephalopathy, ataxia, and developmental delay (PMID: 26947546, 27282648, 27282546). This variant is also known as c.638_639insA in the literature. ClinVar contains an entry for this variant (Variation ID: 31199). Loss-of-function variants in BRAT1 are known to be pathogenic (PMID: 22279524, 25500575). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000268435 SCV000858549 pathogenic not provided 2017-12-05 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000024198 SCV000966181 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 RCV000024198 SCV000996134 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 detected as a homozygous change in individuals with lethal neonatal rigidity and seizure syndrome (PMID: 22279524). It has also been reported in the compound heterozygous state in individuals with milder phenotypes (PMID: 27282648, 27282546). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.024%. Based on the available evidence, the c.638dupA (p.Val214GlyfsTer189) variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000268435 SCV001247246 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
New York Genome Center RCV000677127 SCV001480278 likely pathogenic Neurodevelopmental disorder with cerebellar atrophy and with or without seizures 2019-10-10 criteria provided, single submitter clinical testing
OMIM RCV000024198 SCV000045489 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2012-01-01 no assertion criteria provided literature only
OMIM RCV000677127 SCV000803197 pathogenic Neurodevelopmental disorder with cerebellar atrophy and with or without seizures 2012-01-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000677127 SCV001423323 not provided Neurodevelopmental disorder with cerebellar atrophy and with or without seizures no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 05-31-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV000024198 SCV001427430 pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2019-01-01 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000268435 SCV001744763 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000268435 SCV001807205 pathogenic not provided no assertion criteria provided clinical testing

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