NM_015046.5(SETX):c.[1807A>G;1957C>A] AND Spinocerebellar ataxia autosomal recessive 1

Significance: Pathogenic
ClinVar: RCV000002383

Variant: NM_015046.5(SETX):c.[1807A>G;1957C>A]

Type: Haplotype
Allele: NM_015046.5(SETX):c.1807A>G (p.Asn603Asp) 17332
Type: single nucleotide variant
Location: Chr9: 135205178 - assembly GRCh37
Chr9: 132329791 - assembly GRCh38
References: dbSNP: 116205032
OMIM: 608465.0010
UniProtKB: Q7Z333#VAR_036647
Allele: NM_015046.5(SETX):c.1957C>A (p.Gln653Lys) 38424
Type: single nucleotide variant
Location: Chr9: 135205028 - assembly GRCh37
Chr9: 132329641 - assembly GRCh38
References: dbSNP: 116333061
OMIM: 608465.0010
UniProtKB: Q7Z333#VAR_036648


Disease: Spinocerebellar ataxia autosomal recessive 1


    In an African American mother and daughter with a restricted form of autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Bassuk et al. (2007) identified 2 mutations in cis in the SETX gene: a 1807A-G transition, resulting in an asn603-to-asp (N603D) substitution, and a 1957C-A transversion, resulting in a gln653-to-lys (Q653K) substitution. The mutations occurred in a region adjacent to a putative N-terminal protein interaction domain. Detailed analysis confirmed that the 2 mutations were on the same allele and were part of the same haplotype. Although both mother and daughter had frequent falls, oculomotor deficits, and tremor, neither had peripheral neuropathy or 'head thrusting' associated with horizontal gaze, both of which are classic findings in SCAN2. Bassuk et al. (2007) postulated that the 2 mutations acted synergistically, leading to a dominant-negative mutant protein with partial function and an incomplete phenotype.