Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001195248.2(APTX):c.689dupT(p.Glu232GlyfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
APTX (HGNC:15984): (aprataxin) This gene encodes a member of the histidine triad (HIT) superfamily. The encoded protein may play a role in single-stranded DNA repair through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity. Mutations in this gene have been associated with ataxia-ocular apraxia. Alternatively spliced transcript variants have been identified for this gene.[provided by RefSeq, Aug 2010]
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-32984711-C-CA is Pathogenic according to our data. Variant chr9-32984711-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.689dupT (p.E232Gfs*38) alteration, located in exon 7 (coding exon 5) of the APTX gene, consists of a duplication of T at position 689, causing a translational frameshift with a predicted alternate stop codon after 38 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the APTX c.689dupT alteration was not observed, with coverage at this position. The c.689dupT alteration has been reported in multiple patients in either homozygous or compound heterozygous with a second alteration who present with early onset ataxia with oculomotor apraxia, peripheral neuropathy, and hypoalbuminemia. Genotype-phenotype correlations suggest homozygotes are at an increased risk for inability to walk, early ocular motor apraxia onset less than 15 years of age, and cognitive impairment. This alteration has also been reported as c.689insT and c.689_690insT (Hirano, 2004; Ito, 2005: Yokoseki, 2011). Based on the available evidence, this alteration is classified as pathogenic. -
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Pathogenic:1