ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.453_454insATCTTCTC (p.Leu152fs)

dbSNP: rs727505362
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001386843 SCV001587215 pathogenic Neonatal-onset encephalopathy with rigidity and seizures 2023-12-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu152Ilefs*70) in the BRAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRAT1 are known to be pathogenic (PMID: 22279524, 25500575). This variant is present in population databases (rs727505362, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clinical features of neonatal-lethal rigidity and multifocal seizure syndrome (PMID: 23035047). ClinVar contains an entry for this variant (Variation ID: 1073760). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV002286844 SCV002577305 likely pathogenic not provided 2022-03-29 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25500575, 22279524, 25319849, 26947546, 30346566, 27282648, 27282546, 25937001, 23035047, Fernandez-Jaen2016[Review])
Illumina Laboratory Services, Illumina RCV003314690 SCV004014749 pathogenic Neurodevelopmental disorder with cerebellar atrophy and with or without seizures 2023-04-24 criteria provided, single submitter clinical testing The BRAT1 c.453_454insATCTTCTC (p.Leu152IlefsTer70) frameshift variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in a homozygous state in a female with lethal neonatal rigidity and multifocal seizure syndrome (PMID: 23035047; 25937001). The highest frequency of this allele in the Genome Aggregation Database is 0.000519 in the Latino/Admixed American population (version 2.1.1). Based on the available evidence the c.453_454insATCTTCTC (p.Leu152IlefsTer70) variant is classified as pathogenic for neurodevelopmental disorder with cerebellar atrophy and with or without seizures.
PreventionGenetics, part of Exact Sciences RCV003416308 SCV004117467 likely pathogenic BRAT1-related condition 2022-09-20 criteria provided, single submitter clinical testing The BRAT1 c.453_454insATCTTCTC variant is predicted to result in a frameshift and premature protein termination (p.Leu152Ilefs*70). This variant was reported in homozygous state in an individual with neonatal epilepsy (Saunders et al. 2012. PubMed ID: 23035047). This variant is reported in 0.052% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-2583573-G-GGAGAAGAT). Frameshift variants in BRAT1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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