The p.Trp279X variant in APTX has been reported in 15 families with ataxia-oculo motor apraxia 1. In 12 of the families, affected individuals carried the variant in a homozygous state (Moreira 2001, Barbot 2001, Tranchant 2003, Le Ber 2003), whereas in 2 of the families the patients were compound heterozygotes (Tranchan t 2003, Le Ber 2003). This variant has also been identified in 13/121,084 chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104894103). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 27 9, which is predicted to lead to a truncated or absent protein. Loss of function of the APTX gene is associated with ataxia-oculomotor apraxia 1. In summary, t his variant meets our criteria to be classified as pathogenic for ataxia-oculomo tor apraxia 1 in an autosomal recessive manner based upon biallelic case observa tions, low frequency in control populations and predicted loss of function impac t.
ClinVar Genomic variation as it relates to human health
NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(18)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
18
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)
Variation ID: 4431 Accession: VCV000004431.60
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p21.1 9: 32974495 (GRCh38) [ NCBI UCSC ] 9: 32974493 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 Aug 30, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001195248.2:c.837G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001182177.2:p.Trp279Ter nonsense NM_001195249.2:c.837G>A NP_001182178.1:p.Trp279Ter nonsense NM_001195250.2:c.675G>A NP_001182179.2:p.Trp225Ter nonsense NM_001195251.2:c.837G>A NP_001182180.1:p.Trp279Ter nonsense NM_001195252.2:c.621G>A NP_001182181.2:p.Trp207Ter nonsense NM_001195254.2:c.675G>A NP_001182183.1:p.Trp225Ter nonsense NM_001368995.1:c.837G>A NP_001355924.1:p.Trp279Ter nonsense NM_001368996.1:c.837G>A NP_001355925.1:p.Trp279Ter nonsense NM_001368997.1:c.837G>A NP_001355926.1:p.Trp279Ter nonsense NM_001368998.1:c.837G>A NP_001355927.1:p.Trp279Ter nonsense NM_001368999.1:c.837G>A NP_001355928.1:p.Trp279Ter nonsense NM_001369000.1:c.675G>A NP_001355929.1:p.Trp225Ter nonsense NM_001369001.1:c.675G>A NP_001355930.1:p.Trp225Ter nonsense NM_001369002.1:c.573G>A NP_001355931.1:p.Trp191Ter nonsense NM_001369003.1:c.573G>A NP_001355932.1:p.Trp191Ter nonsense NM_001369004.1:c.573G>A NP_001355933.1:p.Trp191Ter nonsense NM_001369005.1:c.573G>A NP_001355934.1:p.Trp191Ter nonsense NM_001369006.1:c.573G>A NP_001355935.1:p.Trp191Ter nonsense NM_001370669.1:c.573G>A NP_001357598.1:p.Trp191Ter nonsense NM_001370670.1:c.573G>A NP_001357599.1:p.Trp191Ter nonsense NM_001370673.1:c.573G>A NP_001357602.1:p.Trp191Ter nonsense NM_175069.3:c.837G>A NP_778239.2:p.Trp279Ter nonsense NM_175073.3:c.837G>A NP_778243.1:p.Trp279Ter nonsense NR_036577.2:n.788G>A non-coding transcript variant NR_160920.1:n.676G>A non-coding transcript variant NR_160921.1:n.807G>A non-coding transcript variant NR_160922.1:n.1038G>A non-coding transcript variant NR_160923.1:n.842G>A non-coding transcript variant NR_160924.1:n.847G>A non-coding transcript variant NR_160925.1:n.1043G>A non-coding transcript variant NR_160926.1:n.833G>A non-coding transcript variant NR_160927.1:n.926G>A non-coding transcript variant NR_160928.1:n.816G>A non-coding transcript variant NR_160929.1:n.730G>A non-coding transcript variant NR_160930.1:n.783G>A non-coding transcript variant NR_160931.1:n.1022G>A non-coding transcript variant NC_000009.12:g.32974495C>T NC_000009.11:g.32974493C>T NG_012821.2:g.55637G>A - Protein change
- W279*, W225*, W191*, W207*
- Other names
-
p.W279*:TGG>TGA
- Canonical SPDI
- NC_000009.12:32974494:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00038
The Genome Aggregation Database (gnomAD) 0.00044
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| APTX | - | - |
GRCh38 GRCh37 |
289 | 358 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2023 | RCV000004681.23 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2023 | RCV000197775.42 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 22, 2021 | RCV002512761.3 | |
|
APTX-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 23, 2024 | RCV004757946.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
|
Pathogenic
(Aug 26, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280640.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Nov 23, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593268.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Apr 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966879.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Trp279X variant in APTX has been reported in 15 families with ataxia-oculo motor apraxia 1. In 12 of the families, affected individuals carried the … (more)
The p.Trp279X variant in APTX has been reported in 15 families with ataxia-oculo motor apraxia 1. In 12 of the families, affected individuals carried the variant in a homozygous state (Moreira 2001, Barbot 2001, Tranchant 2003, Le Ber 2003), whereas in 2 of the families the patients were compound heterozygotes (Tranchan t 2003, Le Ber 2003). This variant has also been identified in 13/121,084 chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104894103). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 27 9, which is predicted to lead to a truncated or absent protein. Loss of function of the APTX gene is associated with ataxia-oculomotor apraxia 1. In summary, t his variant meets our criteria to be classified as pathogenic for ataxia-oculomo tor apraxia 1 in an autosomal recessive manner based upon biallelic case observa tions, low frequency in control populations and predicted loss of function impac t. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807628.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 strong, PM3 very strong, PP1 strong
Number of individuals with the variant: 1
Clinical Features:
Hypometric saccades (present) , Neurodevelopmental delay (present) , Cerebellar ataxia (present) , Oculomotor apraxia (present) , Central hypotonia (present) , Abnormal cerebellum morphology (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Jan 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018360.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001230811.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs104894103, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Trp279*) in the APTX gene. While … (more)
This variant is present in population databases (rs104894103, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Trp279*) in the APTX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the APTX protein. This premature translational stop signal has been observed in individuals with cerebellar ataxia with oculomotor apraxia (PMID: 11586300, 12629250, 14506070, 15996403, 16700949, 29356829, 29482223). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects APTX function (PMID: 15790557). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 4431). This variant is also known as c.879G>A; p.Trp293*. (less)
|
|
|
Pathogenic
(Sep 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915280.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The APTX c.837G>A (p.Trp279Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, … (more)
The APTX c.837G>A (p.Trp279Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp279Ter variant has been reported in 27 individuals with ataxia with oculomotor apraxia, type 1 (AOA1), including in 19 individuals from 17 families in a homozygous state, in seven individuals from five families in a compound heterozygous state, and in a heterozygous state in one individual in whom a second variant could not be identified (Moreira et al. 2001; Tranchant et al. 2003; Quinzii et al. 2005; Le Ber et al. 2007; Castellotti et al. 2011). The p.Trp279Ter variant was shown to co-segregate with the disease in one family and has been associated with a Portuguese founding haplotype. The variant causes the loss of approximately 19% of the aprataxin protein, including the zinc-finger domain that represents a putative DNA binding site, suggesting it may have a deleterious effect on the protein's proposed role in DNA repair. Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Based on the collective evidence and the potential impact of stop-gained variants, the p.Trp279Ter variant is classified as pathogenic for ataxia with oculomotor apraxia, type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Ataxia-oculomotor apraxia type 1
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251459.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The pathogenic APTX c.837G>A (p.W279*) nonsense variant is predicted to result in nonsense-mediated decay or premature termination of the APTX protein. This variant has been … (more)
The pathogenic APTX c.837G>A (p.W279*) nonsense variant is predicted to result in nonsense-mediated decay or premature termination of the APTX protein. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with ataxia with oculomotor apraxia type 1 (PMID: 11586300; 14506070; 12629250; 15164193; 21465257). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000251159.13
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect indicating that W279X is associated with no Aprataxin activity (Seidle et al., 2005); Nonsense variant in the C-terminus … (more)
Published functional studies demonstrate a damaging effect indicating that W279X is associated with no Aprataxin activity (Seidle et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 64 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 11294920, 16400613, 25989649, 15699391, 11586300, 12629250, 17242337, 21465257, 31493945, 29891053, 15790557, 32750061, 31589614, 30609409, 29482223, 32214227, 15996403, 29913018, 15800456, 32488064, 29356829, 16700949, 29915382, 25525159, 34426522, 15164193, 32769066, 32606550, 33101765) (less)
|
|
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Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000612398.4
First in ClinVar: Mar 08, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant produced protein with lower stability and lower enzymatic activity than wild type (PMID: 15790557). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
|
|
|
Pathogenic
(Mar 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003704992.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.837G>A (p.W279*) alteration, located in exon 8 (coding exon 6) of the APTX gene, consists of a G to A substitution at nucleotide position … (more)
The c.837G>A (p.W279*) alteration, located in exon 8 (coding exon 6) of the APTX gene, consists of a G to A substitution at nucleotide position 837. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 279. This alteration occurs at the 3' terminus of the APTX gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 18% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein stability. Based on data from the Genome Aggregation Database (gnomAD) database, the APTX c.837G>A alteration was observed in 0.02% (51/282248) of total alleles studied, with a frequency of 0.03% (37/128976) in the European (non-Finnish) subpopulation. The c.837G>A (p.W279*) alteration has been reported in over 50 patients with ataxia-oculomotor apraxia either homozygous or compound heterozygous with a second pathogenic allele. This is the most common pathogenic allele in the European population (Le Ber, 2003; Mahajnah, 2005; Moreira, 2001; Renaud, 2018; Tranchant, 2003). Functional analysis demonstrated that the p.W279* alteration results in the absence of protein product in cells and significantly diminishes enzyme activity (Seidle, 2005; Shahwan, 2006). Based on the available evidence, this alteration is classified as pathogenic. (less)
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|
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Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246071.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
ATAXIA, EARLY-ONSET, WITH OCULOMOTOR APRAXIA AND HYPOALBUMINEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024855.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In patients with EAOH (208920) from 5 Portuguese families, Moreira et al. (2001) identified an 837G-A transition in exon 6 of the APTX gene, resulting … (more)
In patients with EAOH (208920) from 5 Portuguese families, Moreira et al. (2001) identified an 837G-A transition in exon 6 of the APTX gene, resulting in a trp279-to-ter (W279X) mutation, in association with a founding haplotype. In an Italian patient with classic EAOH, Tranchant et al. (2003) identified homozygosity for the W279X mutation. Two French sibs were found to have compound heterozygosity for the W279X mutation and a missense mutation. Their phenotype was mild, with later onset of ataxia, no hypoalbuminemia, and no oculomotor apraxia. The authors noted the phenotypic variability and suggested that the missense mutation in the French sibs likely produced a semifunctional protein. Quinzii et al. (2005) identified a homozygous W279X mutation in 3 sibs originally reported by Musumeci et al. (2001) as having familial cerebellar ataxia with muscle coenzyme Q10 (CoQ10) deficiency (see, e.g., COQ10D1, 607426). All 3 patients responded well to CoQ10 supplementation. An affected cousin was heterozygous for the W279X mutation, but the authors suspected he had another mutation. Thirteen additional patients with coenzyme Q deficiency did not have APTX mutations. Quinzii et al. (2006) noted that CoQ10 deficiency has been associated with 3 major clinical phenotypes and remarked that the finding of mutation in the APTX gene in these sibs supports the hypothesis that the ataxic form of CoQ10 deficiency is a genetically heterogeneous entity in which deficiency of CoQ10 can be secondary. Le Ber et al. (2007) found decreased muscle CoQ10 in 5 of 6 patients with AOA1. Three patients who were homozygous for the W279X mutation had the lowest values. The CoQ10 deficiency did not correlate with disease duration, severity, or other blood parameters, and mitochondrial morphology and respiratory function were normal. Castellotti et al. (2011) identified recessive APTX mutations in 13 (6.4%) of 204 Italian probands with progressive cerebellar ataxia. The most common mutation was W279X, which was found in homozygous state in 7 patients and in compound heterozygosity with another pathogenic APTX mutation in 1 patient. (less)
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|
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Pathogenic
(Aug 01, 2019)
|
no assertion criteria provided
Method: research
|
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Affected status: yes
Allele origin:
germline
|
Section for Clinical Neurogenetics, University of Tübingen
Accession: SCV001156079.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807370.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958046.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967704.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Pathogenic
(Sep 23, 2024)
|
no assertion criteria provided
Method: clinical testing
|
APTX-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005366646.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The APTX c.837G>A variant is predicted to result in premature protein termination (p.Trp279*). This variant has been reported to be causative for autosomal recessive ataxia … (more)
The APTX c.837G>A variant is predicted to result in premature protein termination (p.Trp279*). This variant has been reported to be causative for autosomal recessive ataxia with oculomotor apraxia 1 (Moreira et al. 2001. PubMed ID: 11586300; Coutelier et al. 2018. PubMed ID: 29482223). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4431/). Nonsense variants in APTX are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Comment:
Comment:
ACMG classification criteria: PVS1 strong, PM3 very strong, PP1 strong
Comment:
This variant is present in population databases (rs104894103, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Trp279*) in the APTX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the APTX protein. This premature translational stop signal has been observed in individuals with cerebellar ataxia with oculomotor apraxia (PMID: 11586300, 12629250, 14506070, 15996403, 16700949, 29356829, 29482223). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects APTX function (PMID: 15790557). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 4431). This variant is also known as c.879G>A; p.Trp293*.
Comment:
The APTX c.837G>A (p.Trp279Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp279Ter variant has been reported in 27 individuals with ataxia with oculomotor apraxia, type 1 (AOA1), including in 19 individuals from 17 families in a homozygous state, in seven individuals from five families in a compound heterozygous state, and in a heterozygous state in one individual in whom a second variant could not be identified (Moreira et al. 2001; Tranchant et al. 2003; Quinzii et al. 2005; Le Ber et al. 2007; Castellotti et al. 2011). The p.Trp279Ter variant was shown to co-segregate with the disease in one family and has been associated with a Portuguese founding haplotype. The variant causes the loss of approximately 19% of the aprataxin protein, including the zinc-finger domain that represents a putative DNA binding site, suggesting it may have a deleterious effect on the protein's proposed role in DNA repair. Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Based on the collective evidence and the potential impact of stop-gained variants, the p.Trp279Ter variant is classified as pathogenic for ataxia with oculomotor apraxia, type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The pathogenic APTX c.837G>A (p.W279*) nonsense variant is predicted to result in nonsense-mediated decay or premature termination of the APTX protein. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with ataxia with oculomotor apraxia type 1 (PMID: 11586300; 14506070; 12629250; 15164193; 21465257).
Comment:
Published functional studies demonstrate a damaging effect indicating that W279X is associated with no Aprataxin activity (Seidle et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 64 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 11294920, 16400613, 25989649, 15699391, 11586300, 12629250, 17242337, 21465257, 31493945, 29891053, 15790557, 32750061, 31589614, 30609409, 29482223, 32214227, 15996403, 29913018, 15800456, 32488064, 29356829, 16700949, 29915382, 25525159, 34426522, 15164193, 32769066, 32606550, 33101765)
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant produced protein with lower stability and lower enzymatic activity than wild type (PMID: 15790557). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
The c.837G>A (p.W279*) alteration, located in exon 8 (coding exon 6) of the APTX gene, consists of a G to A substitution at nucleotide position 837. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 279. This alteration occurs at the 3' terminus of the APTX gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 18% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein stability. Based on data from the Genome Aggregation Database (gnomAD) database, the APTX c.837G>A alteration was observed in 0.02% (51/282248) of total alleles studied, with a frequency of 0.03% (37/128976) in the European (non-Finnish) subpopulation. The c.837G>A (p.W279*) alteration has been reported in over 50 patients with ataxia-oculomotor apraxia either homozygous or compound heterozygous with a second pathogenic allele. This is the most common pathogenic allele in the European population (Le Ber, 2003; Mahajnah, 2005; Moreira, 2001; Renaud, 2018; Tranchant, 2003). Functional analysis demonstrated that the p.W279* alteration results in the absence of protein product in cells and significantly diminishes enzyme activity (Seidle, 2005; Shahwan, 2006). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The APTX c.837G>A variant is predicted to result in premature protein termination (p.Trp279*). This variant has been reported to be causative for autosomal recessive ataxia with oculomotor apraxia 1 (Moreira et al. 2001. PubMed ID: 11586300; Coutelier et al. 2018. PubMed ID: 29482223). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4431/). Nonsense variants in APTX are expected to be pathogenic. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The p.Trp279X variant in APTX has been reported in 15 families with ataxia-oculo motor apraxia 1. In 12 of the families, affected individuals carried the variant in a homozygous state (Moreira 2001, Barbot 2001, Tranchant 2003, Le Ber 2003), whereas in 2 of the families the patients were compound heterozygotes (Tranchan t 2003, Le Ber 2003). This variant has also been identified in 13/121,084 chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104894103). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This nonsense variant leads to a premature termination codon at position 27 9, which is predicted to lead to a truncated or absent protein. Loss of function of the APTX gene is associated with ataxia-oculomotor apraxia 1. In summary, t his variant meets our criteria to be classified as pathogenic for ataxia-oculomo tor apraxia 1 in an autosomal recessive manner based upon biallelic case observa tions, low frequency in control populations and predicted loss of function impac t.
Comment:
ACMG classification criteria: PVS1 strong, PM3 very strong, PP1 strong
Comment:
This variant is present in population databases (rs104894103, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Trp279*) in the APTX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the APTX protein. This premature translational stop signal has been observed in individuals with cerebellar ataxia with oculomotor apraxia (PMID: 11586300, 12629250, 14506070, 15996403, 16700949, 29356829, 29482223). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects APTX function (PMID: 15790557). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 4431). This variant is also known as c.879G>A; p.Trp293*.
Comment:
The APTX c.837G>A (p.Trp279Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp279Ter variant has been reported in 27 individuals with ataxia with oculomotor apraxia, type 1 (AOA1), including in 19 individuals from 17 families in a homozygous state, in seven individuals from five families in a compound heterozygous state, and in a heterozygous state in one individual in whom a second variant could not be identified (Moreira et al. 2001; Tranchant et al. 2003; Quinzii et al. 2005; Le Ber et al. 2007; Castellotti et al. 2011). The p.Trp279Ter variant was shown to co-segregate with the disease in one family and has been associated with a Portuguese founding haplotype. The variant causes the loss of approximately 19% of the aprataxin protein, including the zinc-finger domain that represents a putative DNA binding site, suggesting it may have a deleterious effect on the protein's proposed role in DNA repair. Control data are unavailable for this variant, which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Based on the collective evidence and the potential impact of stop-gained variants, the p.Trp279Ter variant is classified as pathogenic for ataxia with oculomotor apraxia, type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The pathogenic APTX c.837G>A (p.W279*) nonsense variant is predicted to result in nonsense-mediated decay or premature termination of the APTX protein. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with ataxia with oculomotor apraxia type 1 (PMID: 11586300; 14506070; 12629250; 15164193; 21465257).
Comment:
Published functional studies demonstrate a damaging effect indicating that W279X is associated with no Aprataxin activity (Seidle et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 64 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 11294920, 16400613, 25989649, 15699391, 11586300, 12629250, 17242337, 21465257, 31493945, 29891053, 15790557, 32750061, 31589614, 30609409, 29482223, 32214227, 15996403, 29913018, 15800456, 32488064, 29356829, 16700949, 29915382, 25525159, 34426522, 15164193, 32769066, 32606550, 33101765)
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study showed this variant produced protein with lower stability and lower enzymatic activity than wild type (PMID: 15790557). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Comment:
The c.837G>A (p.W279*) alteration, located in exon 8 (coding exon 6) of the APTX gene, consists of a G to A substitution at nucleotide position 837. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 279. This alteration occurs at the 3' terminus of the APTX gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 18% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein stability. Based on data from the Genome Aggregation Database (gnomAD) database, the APTX c.837G>A alteration was observed in 0.02% (51/282248) of total alleles studied, with a frequency of 0.03% (37/128976) in the European (non-Finnish) subpopulation. The c.837G>A (p.W279*) alteration has been reported in over 50 patients with ataxia-oculomotor apraxia either homozygous or compound heterozygous with a second pathogenic allele. This is the most common pathogenic allele in the European population (Le Ber, 2003; Mahajnah, 2005; Moreira, 2001; Renaud, 2018; Tranchant, 2003). Functional analysis demonstrated that the p.W279* alteration results in the absence of protein product in cells and significantly diminishes enzyme activity (Seidle, 2005; Shahwan, 2006). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The APTX c.837G>A variant is predicted to result in premature protein termination (p.Trp279*). This variant has been reported to be causative for autosomal recessive ataxia with oculomotor apraxia 1 (Moreira et al. 2001. PubMed ID: 11586300; Coutelier et al. 2018. PubMed ID: 29482223). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4431/). Nonsense variants in APTX are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents. | Ababneh NA | PloS one | 2020 | PMID: 32750061 |
| Early Onset Dementia in Ataxia Associated with Ocular Apraxia Type 1 (AOA1). | Aikaterini AI | Annals of Indian Academy of Neurology | 2020 | PMID: 32606550 |
| First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. | Hengel H | European journal of human genetics : EJHG | 2020 | PMID: 32214227 |
| Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel. | Arslan EA | Brain & development | 2020 | PMID: 31493945 |
| Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes. | Coutelier M | JAMA neurology | 2018 | PMID: 29482223 |
| Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1. | Renaud M | JAMA neurology | 2018 | PMID: 29356829 |
| Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients. | Castellotti B | Neurogenetics | 2011 | PMID: 21465257 |
| Ataxia with oculomotor apraxia type 1 (AOA1): clinical and neuropsychological features in 2 new patients and differential diagnosis. | D'Arrigo S | Journal of child neurology | 2008 | PMID: 18403580 |
| Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. | Le Ber I | Neurology | 2007 | PMID: 17242337 |
| Atypical presentation of ataxia-oculomotor apraxia type 1. | Shahwan A | Developmental medicine and child neurology | 2006 | PMID: 16700949 |
| A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. | Quinzii C | American journal of human genetics | 2006 | PMID: 16400613 |
| Familial cognitive impairment with ataxia with oculomotor apraxia. | Mahajnah M | Journal of child neurology | 2005 | PMID: 15996403 |
| Disease-associated mutations inactivate AMP-lysine hydrolase activity of Aprataxin. | Seidle HF | The Journal of biological chemistry | 2005 | PMID: 15790557 |
| Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. | Quinzii CM | Neurology | 2005 | PMID: 15699391 |
| Aprataxin mutations are a rare cause of early onset ataxia in Germany. | Habeck M | Journal of neurology | 2004 | PMID: 15164193 |
| Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. | Le Ber I | Brain : a journal of neurology | 2003 | PMID: 14506070 |
| Phenotypic variability of aprataxin gene mutations. | Tranchant C | Neurology | 2003 | PMID: 12629250 |
| The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. | Moreira MC | Nature genetics | 2001 | PMID: 11586300 |
| Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. | Musumeci O | Neurology | 2001 | PMID: 11294920 |
| Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. | Barbot C | Archives of neurology | 2001 | PMID: 11176957 |
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Text-mined citations for rs104894103 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.