NM_000051.4(ATM):c.2922-1G>T AND Ataxia-telangiectasia syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jun 6, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000667991.3

Allele description [Variation Report for NM_000051.4(ATM):c.2922-1G>T]

NM_000051.4(ATM):c.2922-1G>T

Gene:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.2922-1G>T
HGVS:
  • NC_000011.10:g.108271250G>T
  • NG_009830.1:g.53419G>T
  • NM_000051.3:c.2922-1G>T
  • NM_000051.4:c.2922-1G>TMANE SELECT
  • NM_001351834.2:c.2922-1G>T
  • LRG_135t1:c.2922-1G>T
  • LRG_135:g.53419G>T
  • NC_000011.9:g.108141977G>T
Links:
dbSNP: rs1555084931
NCBI 1000 Genomes Browser:
rs1555084931
Molecular consequence:
  • NM_000051.3:c.2922-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000051.4:c.2922-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001351834.2:c.2922-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000792527Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 29, 2017)
unknownclinical testing

Citation Link,

SCV001394310Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 6, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.

Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, Brunt ER, Peeters EA, Gómez Garcia EB, van der Knaap MS, Lincke CR, Laan LA, Tijssen MA, van Rijn MA, Majoor-Krakauer D, Visser M, van 't Veer LJ, Kleijer WJ, et al.

Hum Mutat. 2012 Mar;33(3):561-71. doi: 10.1002/humu.22016. Epub 2012 Jan 25.

PubMed [citation]
PMID:
22213089

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000792527.1

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

From Invitae, SCV001394310.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects an acceptor splice site in intron 19 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in an individual with clinical features of ataxia-telangiectasia (PMID: 22213089). ClinVar contains an entry for this variant (Variation ID: 490499). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). 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.

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

Last Updated: Oct 30, 2021

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