ClinVar Miner

Submissions for variant NM_001195248.2(APTX):c.837G>A (p.Trp279Ter) (rs104894103)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000197775 SCV000612398 pathogenic not provided 2016-03-04 criteria provided, single submitter clinical testing
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
GeneDx RCV000197775 SCV000251159 pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing The W279X nonsense variant in the APTX gene has been reported previously in association with ataxia with oculomotor apraxia in several unrelated families and is one of the most common pathogenic variants identified in various European populations (Moreira et al., 2001; Seidle et al., 2005; Castellotti et al., 2011). The W279X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant is predicted to cause loss of normal protein function through protein truncation. Functional analysis found that W279X is associated with no Aprataxin activity (Seidle et al. 2005). In summary, we interpret this variant as pathogenic.
Genetic Services Laboratory, University of Chicago RCV000004681 SCV000593268 pathogenic Ataxia-oculomotor apraxia type 1 2015-11-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000004681 SCV000915280 pathogenic Ataxia-oculomotor apraxia type 1 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,Partners HealthCare Personalized Medicine RCV000004681 SCV000966879 pathogenic Ataxia-oculomotor apraxia type 1 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.
OMIM RCV000004681 SCV000024855 pathogenic Ataxia-oculomotor apraxia type 1 2011-08-01 no assertion criteria provided literature only

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