ClinVar

Description

This sequence change in SOD1 is predicted to replace aspartic acid with alanine at codon 91, p.(Asp91Ala). Historically this variant is known as p.(Asp90Ala) or p.D90A. The apartic acid residue is weakly conserved (100 vertebrates, UCSC), and is located in the Sod Cu domain. There is a large physicochemical difference between aspartic acid and alanine. The highest population minor allele frequency in gnomAD v2.1 is 1.2% (298/25,122 alleles, 3 homozygotes) in the Finnish population. Whereas, the highest continental population minor allele frequency in gnomAD v2.1 is 0.07% (96/129,186 alleles, 1 homozygote) in the European (non-Finnish) population. The homozygous individuals are absent from the non-neuro cohort in gnomAD v2.1. The variant is one of the most commonly reported SOD1 variants associated with amyotrophic lateral sclerosis (ALS) and is a Scandinavian founder, which shows both autosomal dominant and recessive patterns in different populations (PMID: 9817920, 12442272). The prevalence of the heterozygous variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 2.82, 95% CI: 1.40-5.67) (PMID: 19965850, 23100398, 28105640, 28222900, 28430856, 28444446; gnomAD v2.1 European non-Finnish non-neuro cohort). This variant has been detected in the homozygous state in many individuals with ALS and compound heterozygous with a second allele in at two affected families (PMID: 7647793, 11220750, 34668453). The recessive and dominant kindreds reported with the variant share a rare haplotype, however a recessive founder arose subsequently through a recombination event. The homozygous phenotype is characterised by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary (PMID: 12442272). In recessive kindreds segregation with ALS is reported in homozygous individuals and heterozygous individuals are unaffected (PMID: 7647793, 12442272). Whereas, in dominant kindreds segregation of the heterozygous variant with disease is reported with incomplete penetrance (PMID: 8909456, 10809943). A homozygous mouse model recapitulates the human ALS phenotype (PMID: 17146286). Multiple lines of computational evidence have conflicting predictions for the missense substitution (5/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PP1_Strong, PM3, PS4_Supporting.