NM_001195248.2(APTX):c.596del (p.Arg199fs) AND Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 28, 2019
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:: RCV001784753.7

Allele description [Variation Report for NM_001195248.2(APTX):c.596del (p.Arg199fs)]

NM_001195248.2(APTX):c.596del (p.Arg199fs)

Gene:

APTX:aprataxin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

9p21.1

Genomic location:

Preferred name:

NM_001195248.2(APTX):c.596del (p.Arg199fs)

HGVS:

NC_000009.12:g.32984805del
NG_012821.2:g.45327del
NM_001195248.2:c.596delMANE SELECT
NM_001195249.2:c.596del
NM_001195250.2:c.434del
NM_001195251.2:c.596del
NM_001195252.2:c.380del
NM_001195254.2:c.434del
NM_001368995.1:c.596del
NM_001368996.1:c.596del
NM_001368997.1:c.596del
NM_001368998.1:c.596del
NM_001368999.1:c.596del
NM_001369000.1:c.434del
NM_001369001.1:c.434del
NM_001369002.1:c.332del
NM_001369003.1:c.332del
NM_001369004.1:c.332del
NM_001369005.1:c.332del
NM_001369006.1:c.332del
NM_001370669.1:c.332del
NM_001370670.1:c.332del
NM_001370673.1:c.332del
NM_175069.3:c.596del
NM_175073.3:c.596del
NP_001182177.2:p.Arg199fs
NP_001182178.1:p.Arg199fs
NP_001182179.2:p.Arg145fs
NP_001182180.1:p.Arg199fs
NP_001182181.2:p.Arg127fs
NP_001182183.1:p.Arg145fs
NP_001355924.1:p.Arg199fs
NP_001355925.1:p.Arg199fs
NP_001355926.1:p.Arg199fs
NP_001355927.1:p.Arg199fs
NP_001355928.1:p.Arg199fs
NP_001355929.1:p.Arg145fs
NP_001355930.1:p.Arg145fs
NP_001355931.1:p.Arg111fs
NP_001355932.1:p.Arg111fs
NP_001355933.1:p.Arg111fs
NP_001355934.1:p.Arg111fs
NP_001355935.1:p.Arg111fs
NP_001357598.1:p.Arg111fs
NP_001357599.1:p.Arg111fs
NP_001357602.1:p.Arg111fs
NP_778239.2:p.Arg199fs
NP_778243.1:p.Arg199fs
NC_000009.11:g.32984803del
NM_175069.3:c.596delG
NM_175073.2:c.596del
NR_036577.2:n.547del
NR_160921.1:n.566del
NR_160922.1:n.797del
NR_160923.1:n.601del
NR_160924.1:n.606del
NR_160925.1:n.802del
NR_160926.1:n.592del
NR_160930.1:n.542del
NR_160931.1:n.781del

Protein change:

R111fs

Links:

dbSNP: rs770007531

NCBI 1000 Genomes Browser:

rs770007531

Molecular consequence:

NM_001195248.2:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195249.2:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195250.2:c.434del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195251.2:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195252.2:c.380del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001195254.2:c.434del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368995.1:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368996.1:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368997.1:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368998.1:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001368999.1:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369000.1:c.434del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369001.1:c.434del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369002.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369003.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369004.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369005.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001369006.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370669.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370670.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370673.1:c.332del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_175069.3:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_175073.3:c.596del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_036577.2:n.547del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160921.1:n.566del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160922.1:n.797del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160923.1:n.601del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160924.1:n.606del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160925.1:n.802del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160926.1:n.592del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160930.1:n.542del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_160931.1:n.781del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Synonyms:: Ataxia-oculomotor apraxia syndrome; Ataxia-telangiectasia-like syndrome; Early-onset cerebellar ataxia with hypoalbuminemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008842; MedGen: C1859598; Orphanet: 1168; OMIM: 208920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002018349	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003845983	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29356829, 25741868
SCV005060978	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002018349

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 28, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003845983

Lifecell International Pvt. Ltd

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005060978

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

Renaud M, Moreira MC, Ben Monga B, Rodriguez D, Debs R, Charles P, Chaouch M, Ferrat F, Laurencin C, Vercueil L, Mallaret M, M'Zahem A, Pacha LA, Tazir M, Tilikete C, Ollagnon E, Ochsner F, Kuntzer T, Jung HH, Beis JM, Netter JC, Djamshidian A, et al.

JAMA Neurol. 2018 Apr 1;75(4):495-502. doi: 10.1001/jamaneurol.2017.4373.

PubMed [citation]

PMID:: 29356829
PMCID:: PMC5933354

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Revvity Omics, Revvity, SCV002018349.3

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

#	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

From Lifecell International Pvt. Ltd, SCV003845983.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Homozygote Frameshift variant c.596delG in Exon 6 of the APTX gene that results in the amino acid substitution p.Arg199fs*15 was identified. The observed variant has a minor allele frequency of 0.00002% in gnomAD exomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (variant ID: 1323370). This variant was reported among the patients for ataxia with oculomotor apraxia (Renaud M et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005060978.1

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

Description

The observed frameshift c.596del(p.Arg199LeufsTer15) variant in APTX gene has been reported previously in homozygous state in multiple individuals affected with early-onset ataxia with oculomotor apraxia and hypoalbuminemia (Renaud M, et al., 2018). The p.Arg199LeufsTer15 variant has been reported with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Arginine 199, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Arg199LeufsTer15. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jun 17, 2024

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