NM_152743.4(BRAT1):c.2023del (p.Tyr675fs) AND Rigidity and multifocal seizure syndrome, lethal neonatal

Clinical significance:Pathogenic (Last evaluated: Aug 31, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001385214.1

Allele description [Variation Report for NM_152743.4(BRAT1):c.2023del (p.Tyr675fs)]

NM_152743.4(BRAT1):c.2023del (p.Tyr675fs)

Gene:
BRAT1:BRCA1 associated ATM activator 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
7p22.3
Genomic location:
Preferred name:
NM_152743.4(BRAT1):c.2023del (p.Tyr675fs)
HGVS:
  • NC_000007.14:g.2538512del
  • NG_032167.1:g.22247del
  • NM_001350626.2:c.2203del
  • NM_001350627.2:c.1498del
  • NM_152743.4:c.2023delMANE SELECT
  • NP_001337555.1:p.Tyr735fs
  • NP_001337556.1:p.Tyr500fs
  • NP_689956.2:p.Tyr675fs
  • NC_000007.13:g.2578146del
  • NR_146879.2:n.2206del
Protein change:
Y500fs
Molecular consequence:
  • NM_001350626.2:c.2203del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350627.2:c.1498del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_152743.4:c.2023del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_146879.2:n.2206del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL)
Identifiers:
MONDO: MONDO:0013784; MedGen: C3281029; Orphanet: 435845; OMIM: 614498

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001584979Invitaecriteria provided, single submitter
Pathogenic
(Aug 31, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

BRAT1-associated neurodegeneration: Intra-familial phenotypic differences in siblings.

Smith NJ, Lipsett J, Dibbens LM, Heron SE.

Am J Med Genet A. 2016 Nov;170(11):3033-3038. doi: 10.1002/ajmg.a.37853. Epub 2016 Aug 2.

PubMed [citation]
PMID:
27480663

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001584979.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change results in a premature translational stop signal in the BRAT1 gene (p.Tyr675Metfs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acids of the BRAT1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRAT1-related conditions. This variant disrupts the C-terminus of the BRAT1 protein. Other variant(s) that disrupt this region (p.Phe709Thrfs*17) have been determined to be pathogenic (PMID: 27480663). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 14, 2021

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