NM_000051.3(ATM):c.9023G>A (p.Arg3008His) AND Ataxia-telangiectasia syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 11, 2016
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:: RCV000196159.2

Allele description

NM_000051.3(ATM):c.9023G>A (p.Arg3008His)

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_000051.3(ATM):c.9023G>A (p.Arg3008His)

HGVS:

NC_000011.10:g.108365360G>A
NG_009830.1:g.147529G>A
NM_000051.3:c.9023G>A
NP_000042.3:p.Arg3008His
LRG_135t1:c.9023G>A
LRG_135:g.147529G>A
LRG_135p1:p.Arg3008His
NC_000011.9:g.108236087G>A
Q13315:p.Arg3008His
p.R3008H

Protein change:

R3008H

Links:

UniProtKB: Q13315#VAR_010894; dbSNP: rs587781894

NCBI 1000 Genomes Browser:

rs587781894

Allele Frequency:

0.00001(A)

Molecular consequence:

NM_000051.3:c.9023G>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:: MedGen: C0004135; Orphanet: 100; OMIM: 208900

Recent activity

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RecName: Full=Caspase-5; Short=CASP-5; AltName: Full=ICE(rel)-III; AltName: Full...
RecName: Full=Caspase-5; Short=CASP-5; AltName: Full=ICE(rel)-III; AltName: Full=Protease ICH-3; AltName: Full=Protease TY; Contains: RecName: Full=Caspase-5 subunit p20; Contains: RecName: Full=Caspase-5 subunit p10; Flags: Precursor
gi|294862523|sp|P51878.3|CASP5_HUMA

Protein
Trachycephalus quadrangulum voucher QCAZ39782 12S ribosomal RNA gene, partial se...
Trachycephalus quadrangulum voucher QCAZ39782 12S ribosomal RNA gene, partial sequence; mitochondrial
gi|1127299389|gb|KY013386.1|

Nucleotide
ZNF280D [Notechis scutatus]
ZNF280D [Notechis scutatus]
Gene ID:113421620

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000253673	Invitae,	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 11, 2016)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000253673

Invitae,

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 11, 2016)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Invitae,, SCV000253673.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This sequence change replaces arginine with histidine at codon 3008 of the ATM protein (p.Arg3008His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587781894, ExAC <0.01%). This variant has been reported in an individual with ataxia-telangiectasia (A-T) in combination with a pathogenic (p.Arg1466*) variant (PMID: 21665257). This variant has also been reported in an individual with breast cancer (PMID: 19404735). ClinVar contains an entry for this variant (Variation ID: 141634). This variant has also been reported in tumor cell samples from individuals with chronic lymphocytic leukemia, mantle cell lymphoma and malignant B-cell lymphoma with either a 11q deletion or with a pathogenic ATM variant (PMID: 17968022, 21933854, 23585524, 12697903, 10397742, 11756177). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg3008Cys) has been determined to be pathogenic (PMID: 9872980, 10817650, 12552566, 15101044, 18573109, 19431188). This suggests that the arginine residue is critical for ATM protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 19, 2017

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