ClinVar

Description

Variant summary: SPAST c.1625A>G (p.Asp542Gly) results in a non-conservative amino acid change located in the AAA ATPase, AAA+ lid domain (IPR041569) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 249664 control chromosomes (114 heterozygous individuals), suggesting it is unlikely to be strongly associated with a highly penetrant autosomal dominant condition with an early age of onset and may instead be a benign polymorphism. Although, it has been reported that the age of onset and the severity of Autosomal Dominant Spastic Paraplegia 4 are variable, without complete penetrance (e.g. Parodi_2018). c.1625A>G has been reported in the literature in individuals affected with various neurological phenotypes including spastic paraplegia (e.g. Magariello_2010, de Bot_2011, D'Amore_2018, Parodi_2018), amyotrophic lateral sclerosis (e.g. Brugman_2005, Bartoletti-Stella_2021, Grassano_2022), motor neuron disease (Lee_2014), multiple sclerosis (Jia_2018), mitochondrial disorders (DaRe_2013), and cerebral palsy (van Eyk_2021), in most cases without strong evidence for causality. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31134136, 16240363, 30564185, 24215330, 29908077, 25326637, 19875132, 20562464, 30476002, 33770234, 34531397, 35896380). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as VUS (n=3), likely benign (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.