ClinVar Miner

Submissions for variant NM_152743.4(BRAT1):c.2125_2128del (p.Phe709fs) (rs763527391)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414532 SCV000491505 likely pathogenic not provided 2016-06-15 criteria provided, single submitter clinical testing The c.2125_2128delTTTG variant in the BRAT1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Phenylalanine 709, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Phe709ThrfsX17. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 113 amino acids of the protein are replaced by 16 incorrect amino acids. The c.2125_2128delTTTG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2125_2128delTTTG variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000528948 SCV000652251 likely pathogenic Rigidity and multifocal seizure syndrome, lethal neonatal 2019-06-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRAT1 gene (p.Phe709Thrfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acids of the BRAT1 protein. This variant is present in population databases (rs763527391, ExAC 0.009%). This variant has been reported as compound heterozygous with a different variant in BRAT1, c.1857G>A (p.Trp619*), in 2 siblings affected with a BRAT1-associated neurodegenerative disorder (PMID: 27480663). This variant has also been observed in one individual from a cohort that underwent whole genome sequencing (PMID: 29431110) ClinVar contains an entry for this variant (Variation ID: 372962). This variant disrupts the C-terminus of the BRAT1 protein. Other variant(s) that disrupt this region (p.Ser747Thrfs*36) have been observed in individuals with BRAT1-related conditions (PMID:28752061). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000624671 SCV000741707 likely pathogenic Inborn genetic diseases 2017-01-26 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414532 SCV001247245 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265553 SCV001443707 pathogenic BRAT1-associated neurodegenerative disorder 2020-01-07 criteria provided, single submitter clinical testing This frameshifting variant in exon 14 of BRAT1 introduces a premature stop codon and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in the compound heterozygous state in patients with BRAT1-associated neurodegenerative disorder (PMID: 27480663, 30552426). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/250228) and thus is presumed to be rare. Based on the available evidence, the c.2125_2128del (p.Phe709ThrfsTer17) variant is classified as Pathogenic.

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