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NM_000051.4(ATM):c.7307+1G>A AND Ataxia-telangiectasia syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Nov 22, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001377732.16

Allele description [Variation Report for NM_000051.4(ATM):c.7307+1G>A]

NM_000051.4(ATM):c.7307+1G>A

Genes:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.7307+1G>A
HGVS:
  • NC_000011.10:g.108329239G>A
  • NG_009830.1:g.111408G>A
  • NG_054724.1:g.145594C>T
  • NM_000051.4:c.7307+1G>AMANE SELECT
  • NM_001330368.2:c.641-20168C>T
  • NM_001351110.2:c.*38+5981C>T
  • NM_001351834.2:c.7307+1G>A
  • LRG_135t1:c.7307+1G>A
  • LRG_135:g.111408G>A
  • NC_000011.9:g.108199966G>A
  • NM_000051.3:c.7307+1G>A
Links:
dbSNP: rs2086003529
NCBI 1000 Genomes Browser:
rs2086003529
Molecular consequence:
  • NM_001330368.2:c.641-20168C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.*38+5981C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.4:c.7307+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001351834.2:c.7307+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001575133Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Nov 28, 2022)
germlineclinical testing

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

SCV005726014Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Nov 22, 2024)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

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

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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575133.4

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

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1066672). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 15880721). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 49 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005726014.1

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

Description

Variant summary: ATM c.7307+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ATM function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing (Bueno-Martinez_2022). The variant was absent in 248522 control chromosomes (gnomAD). c.7307+1G>A has been reported in the literature in multiple compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Birrell_2005, Soukupova_2011). The following publications have been ascertained in the context of this evaluation (PMID: 15880721, 21833744, 35716007). ClinVar contains an entry for this variant (Variation ID: 1066672). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Feb 16, 2025