ClinVar Genomic variation as it relates to human health

Variable age of onset and penetrance within families reported for SPG4 (PMID: 30476002).

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

SPAST: PP2, BS1

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant is associated with the following publications: (PMID: 24215330, 19875132, 30564185, 20562464, 17971434, 16240363, 25326637, 31134136, 30476002)

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.