Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_001195248.2(APTX):āc.837G>Cā(p.Trp279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W279R) has been classified as Pathogenic.
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]