ClinVar Genomic variation as it relates to human health

The p.Arg193Gln (NM_000048.3 c.578G>A) variant in ASL has been reported in 7 com pound heterozygous individuals and 1 homozygous individual with clinical feature s of argininosuccinate lyase deficiency (Barbosa 1991, Kleijer 2002, Linnebank 2 002, and Balmer 2014). This variant has also been identified in 2/22,098 of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs373697663). In vitro functional studies provide some evidenc e that this variant may impact protein function (Hu 2014); however these types o f assays may not accurately represent biological function. This variant has also been reported in ClinVar (Variation ID#372306). In summary, although additiona l studies are required to fully establish its clinical significance, the p.Arg19 3Gln variant is likely pathogenic for ASL in an autosomal recessive manner based on biallelic observations in patients, impact in functional studies, and low po pulation frequency.

Variant summary: ASL c.578G>A (p.Arg193Gln) results in a conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) 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 2e-05 in 201534 control chromosomes. c.578G>A has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria, and was reported confirmed in trans in at least one patient (example Balmer_2014, Kleijer_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant impacting the same amino acid has been reported in HGMD in association with Argininosuccinate lyase deficiency and has been classified as pathogenic by at least one lab in ClinVar (p.R193W). Six ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=4) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 193 of the ASL protein (p.Arg193Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 705937, 12408190, 24166829). ClinVar contains an entry for this variant (Variation ID: 372306). 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 ASL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 25778938). This variant disrupts the p.Arg193 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 24166829), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); 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: 12408190, 12384776, 1705937, 24166829, 30609409, 31709144, 31943503)