NM_000051.4(ATM):c.192del (p.Leu64fs) AND Ataxia-telangiectasia syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Apr 4, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000231922.5

Allele description [Variation Report for NM_000051.4(ATM):c.192del (p.Leu64fs)]

NM_000051.4(ATM):c.192del (p.Leu64fs)

Gene:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.192del (p.Leu64fs)
HGVS:
  • NC_000011.10:g.108229184del
  • NG_009830.1:g.11353del
  • NM_000051.3:c.192del
  • NM_000051.4:c.192delMANE SELECT
  • NM_001351834.2:c.192del
  • NM_001351835.2:c.192del
  • NM_001351836.2:c.192del
  • NP_000042.3:p.Leu64fs
  • NP_000042.3:p.Leu64fs
  • NP_001338763.1:p.Leu64fs
  • NP_001338764.1:p.Leu64fs
  • NP_001338765.1:p.Leu64fs
  • LRG_135t1:c.192del
  • LRG_135:g.11353del
  • LRG_135p1:p.Leu64fs
  • NC_000011.9:g.108099911del
  • NM_000051.3:c.192delA
Protein change:
L64fs
Links:
dbSNP: rs878853490
NCBI 1000 Genomes Browser:
rs878853490
Molecular consequence:
  • NM_000051.3:c.192del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_000051.4:c.192del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001351834.2:c.192del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001351835.2:c.192del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001351836.2:c.192del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Ataxia-telangiectasia syndrome (AT)
Synonyms:
Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000282885Invitaecriteria provided, single submitter
Pathogenic
(Apr 4, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000486595Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 30, 2016)
unknownclinical testing

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000918565Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Sep 28, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

Ten new ATM alterations in Polish patients with ataxia-telangiectasia.

Podralska MJ, Stembalska A, Ślęzak R, Lewandowicz-Uszyńska A, Pietrucha B, Kołtan S, Wigowska-Sowińska J, Pilch J, Mosor M, Ziółkowska-Suchanek I, Dzikiewicz-Krawczyk A, Słomski R.

Mol Genet Genomic Med. 2014 Nov;2(6):504-11. doi: 10.1002/mgg3.98. Epub 2014 Jul 30.

PubMed [citation]
PMID:
25614872
PMCID:
PMC4303220

Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.

Huang Y, Yang L, Wang J, Yang F, Xiao Y, Xia R, Yuan X, Yan M.

Neuromolecular Med. 2013 Sep;15(3):536-40. doi: 10.1007/s12017-013-8240-3. Epub 2013 Jun 27. Erratum in: Neuromolecular Med. 2014 Mar;16(1):216.

PubMed [citation]
PMID:
23807571
PMCID:
PMC3732755
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000282885.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change deletes 1 nucleotide from exon 4 of the ATM mRNA (c.192delA), causing a frameshift at codon 64. This creates a premature translational stop signal (p.Leu64Phefs*12) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.

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

From Counsyl, SCV000486595.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918565.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: ATM c.192delA (p.Leu64PhefsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Glu73fsX26, p.Tyr171X, p.Tyr264fsX12). The variant was absent in 273852 control chromosomes. To our knowledge, no occurrence of c.192delA in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Oct 30, 2021

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