Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_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 (★). Synonymous variant affecting the same amino acid position (i.e. V230V) has been classified as Benign. 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]
APTX Gene-Disease associations (from GenCC):
ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
Our verdict: Pathogenic. The variant received 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 9-32984711-C-CA is Pathogenic according to our data. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars.
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 hypoalbuminemiaPathogenic:1