Submissions for variant NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)

gnomAD frequency: 0.00044  dbSNP: rs104894103

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197775	SCV000251159	pathogenic	not provided	2022-01-26	criteria provided, single submitter	clinical testing	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)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000197775	SCV000280640	pathogenic	not provided	2014-08-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000004681	SCV000593268	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2015-11-23	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000197775	SCV000612398	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000004681	SCV000915280	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2017-09-08	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004681	SCV000966879	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2016-04-27	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000197775	SCV001230811	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing	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*.
CeGaT Center for Human Genetics Tuebingen	RCV000197775	SCV001246071	pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000004681	SCV001251459	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia		criteria provided, single submitter	research	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).
Revvity Omics, Revvity	RCV000004681	SCV002018360	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2021-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512761	SCV003704992	pathogenic	Inborn genetic diseases	2021-03-22	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000004681	SCV003807628	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2023-01-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PM3 very strong, PP1 strong
OMIM	RCV000004681	SCV000024855	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2011-08-01	no assertion criteria provided	literature only
Section for Clinical Neurogenetics, University of Tübingen	RCV000004681	SCV001156079	pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2019-08-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000197775	SCV001807370	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000197775	SCV001958046	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000197775	SCV001967704	pathogenic	not provided		no assertion criteria provided	clinical testing