ClinVar Genomic variation as it relates to human health

Variant summary: ACY1 c.1057C>T (p.Arg353Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251440 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. Due to the extremely low prevalence of this condition, this frequency does not allow conclusions about variant significance. Furthermore, the clinical/biochemical phenotype, family history or follow-up on the two homozygous individuals reported in the gnomAD database is not known. c.1057C>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Aminoacylase I deficiency supported by characteristic biochemical organic acid profiles (example, Van Coster_2005, Tylki-Szymanska_2010, Sass_2016). The age of presentation was variable ranging from newborn stage for two homozygous case reports (Van Coster_2005, Tylki-Szymanska_2010) to a 63 year old compound heterozygous woman with dystonic symptoms starting at age 12 (example, Sass_2016). These data indicate that the variant is likely to be associated with disease. However, the possibility of ACY1 deficiency having a pathogenic significance with pleiotropic clinical expression versus simply a biochemical variant phenotype has been speculated (Sass_2006). At least one publication reports experimental evidence evaluating an impact on protein function (example Van Coster_2005). The most pronounced variant effect results in <1% of normal Aminoacylase I enzyme activity in lymphoblasts from a homozygous individual. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely Pathogenic, n=5; VUS, n=5) presumably attributed to variability in interpreting the frequency of this variant in population databases. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The c.1057C>T (p.R353C) alteration is located in exon 14 (coding exon 13) of the ACY1 gene. This alteration results from a C to T substitution at nucleotide position 1057, causing the arginine (R) at amino acid position 353 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.27% (770/282836) total alleles studied, including 4 homozygotes. The highest observed frequency was 0.41% (534/129150) of European (non-Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous state in several individuals with aminoacylase 1 deficiency (Van Coster, 2005; Sass, 2006; Sass, 2007; Tylki-Szymanska, 2010; Sass, 2015). In HEK293 cells, this variant demonstrated a loss of enzyme activity and no protein was detected by western blot compared to wild type (Sommer, 2011). Based on the available evidence, this alteration is classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 353 of the ACY1 protein (p.Arg353Cys). This variant is present in population databases (rs121912698, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with aminoacylase 1 deficiency (PMID: 16274666, 16465618, 17562838, 20480396, 26686503). ClinVar contains an entry for this variant (Variation ID: 18110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACY1 protein function. Experimental studies have shown that this missense change affects ACY1 function (PMID: 21414403, 26686503). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.Arg353Cys variant in ACY1 has been reported in at least 5 homozygous and 2 compound heterozygous individuals with aminoacylase 1 deficiency, including one homozygous individual with an additional finding of Menkes disease (Tylki-Szymanska 2010 PMID: 20480396, Sass 2007 PMID: 17562838, Sass 2006 PMID: 16465618, van Coster 2005 PMID: 16274666, Mauri 2023 PMID: 36936426). There was little consistency in the phenotypes of these individuals or in the severity of the phenotypes, aside from some neurological involvement. This variant has also been It has also been reported by other clinical laboratories in ClinVar (Variation ID 18110) and has been identified in 0.39% (271/68042) European chromosomes by gnomAD (https://gnomad.broadinstitute.org/, v3.1.2), including in 4 homozygous individuals (v2.1.1). In vitro functional studies support an impact on protein function, where HEK cells with the variant show a loss of enzyme activity and no ACY1 protein detection on a western blot compared to wildtype (Sommer 2011 PMID: 21414403), and lymphoblast cell lines generated from a homozygous patient with this variant show <1% of normal aminoacylase I enzyme activity (van Coster 2005 PMID: 16274666). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive aminoacylase 1 deficiency. ACMG/AMP criteria applied: PM3_Strong, PS3_Moderate.