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NM_000051.4(ATM):c.3284G>A (p.Arg1095Lys) AND Ataxia-telangiectasia syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 28, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001037119.9

Allele description [Variation Report for NM_000051.4(ATM):c.3284G>A (p.Arg1095Lys)]

NM_000051.4(ATM):c.3284G>A (p.Arg1095Lys)

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.3284G>A (p.Arg1095Lys)
Other names:
NM_000051.3(ATM):c.3284G>A; p.Arg1095Lys
HGVS:
  • NC_000011.10:g.108272852G>A
  • NG_009830.1:g.55021G>A
  • NM_000051.4:c.3284G>AMANE SELECT
  • NM_001351834.2:c.3284G>A
  • NP_000042.3:p.Arg1095Lys
  • NP_000042.3:p.Arg1095Lys
  • NP_001338763.1:p.Arg1095Lys
  • LRG_135t1:c.3284G>A
  • LRG_135:g.55021G>A
  • LRG_135p1:p.Arg1095Lys
  • NC_000011.9:g.108143579G>A
  • NM_000051.3:c.3284G>A
  • p.R1095K
Protein change:
R1095K
Links:
dbSNP: rs587781815
NCBI 1000 Genomes Browser:
rs587781815
Molecular consequence:
  • NM_000051.4:c.3284G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.3284G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001200517Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Oct 28, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001200517.5

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

Description

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1095 of the ATM protein (p.Arg1095Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587781815, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 141522). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 22 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: Sep 29, 2024