ClinVar Genomic variation as it relates to human health

The FAR1 c.1438C>T (p.Arg480Cys) variant is a missense variant that has been identified in one study in a heterozygous state in seven individuals with clinical features that include spastic paraparesis, bilateral cataracts, developmental delay, and seizures (Ferdinandusse et al. 2021). The same study also identified two other variants at amino acid residue Arg480, p.Arg480His and p.Arg480Leu, in four patients and one patient, respectively (Ferdinandusse et al. 2021). Inheritance was confirmed to be de novo in all cases. The p.Arg480Cys is not found in the Genome Aggregation Database (version 2.1.1 or version 3.1.1) in a region of good sequence coverage, so the variant is presumed to be rare. Functional studies using fibroblasts from one patient that carried the p.Arg480Cys variant demonstrated increased plasmalogen levels and FAR1 enzymatic activity, elevated ether lipid synthesis, and altered lipome composition (Ferdinandusse et al. 2021). Based on the collective evidence, the p.Arg480Cys variant is classified as pathogenic for autosomal dominant FAR1-related neurodevelopmental disorder.

This is a nonsynonymous variant in the FAR1 gene (OMIM 616107). Heterozygous pathogenic variants in this gene have been associated with autosomal dominant cataracts, spastic paraparesis, and speech delay (CSPSD). This variant was identified de novo in this individual (PS2). This variant has been reported in the heterozygous state in multiple unrelated affected individuals (PMID: 33239752) (PS4). All reported pathogenic variants associated with CSPSD have been de novo missense substitutions of the same amino acid residue (Arg480) (PMID: 33239752) (PM1). Functional studies have shown that this variant leads to increased FAR1 enzymatic activity and increased plasmalogen levels, consistent with a gain-of-function disease mechanism (PMID: 33239752) (PS3_Moderate). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2_Supporting). Based on current evidence, this variant is classified as pathogenic for autosomal dominant CSPSD.

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33239752)

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 423867). This missense change has been observed in individual(s) with autosomal dominant FAR1-related conditions (PMID: 33239752; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 480 of the FAR1 protein (p.Arg480Cys). This variant disrupts the p.Arg480 amino acid residue in FAR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33239752). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.