ClinVar

In all 3 affected members tested from an Italian family with SPG3A (182600), D'Amico et al. (2004) identified a heterozygous mutation in exon 12 of the atlastin gene, resulting in an arg415-to-trp (R415W) substitution. The mutation was not identified in 400 control chromosomes. The 3 patients had onset before 5 years of age, and 2 additional family members were reportedly affected by infantile-onset spastic paraparesis. However, 9 asymptomatic relatives ranging in age from 13 to 70 years also had the mutation. D'Amico et al. (2004) concluded that the reduced penetrance of this mutation indicated that modulator genes or epigenetic factors are involved in the development of the disease, and they noted the implications for genetic counseling.

Varga et al. (2013) identified a heterozygous c.1243C-T transition in the ATL1 gene resulting in an R415W substitution in affected members of a family with SPG3A originally reported by Raggio et al. (1973) as having a pure spastic paraplegia transmitted in an X-linked pattern of inheritance. Whole-exome sequencing of 1 of the affected males identified the heterozygous R415W substitution. This mutation was then identified in 3 affected family members and in 3 unaffected family members, consistent with incomplete penetrance. Two of the unaffected carriers were women, and family history indicated that most unaffected women were obligate carriers. These findings were consistent with sex-associated reduced penetrance of this mutation. Varga et al. (2013) identified the same mutation in 1 of 83 Spanish patients with apparent sporadic HSP and in 2 of 28 Russian patients with dominant HSP. Evidence again suggested incomplete penetrance in these families. Varga et al. (2013) also identified a heterozygous c.1244A-G transition, resulting in an arg415-to-gln (R415Q; 606439.0014) substitution, in a Moroccan family with SPG3A and incomplete penetrance. Varga et al. (2013) noted that both the c.1243C-T and c.1244A-G transitions occur at a CpG nucleotide (on the plus and minus strands, respectively) and thus may represent a mutation hotspot due to spontaneous deamination of methylated cytosines. R415 affects a highly conserved residue that does not localize to a known protein domain.