ClinVar Genomic variation as it relates to human health

The homozygous p.Arg550His variant in ASNS was identified by our study in one individual with Asparagine Synthetase Deficiency. This variant has been identified in the literature in the case of one homozygous affected proband (Galada et al. 2018; PMID: 29405484). Another homozygous affected proband was reported in the literature (Faoucher et al. 2017). This variant has been identified in <0.01% (2/24030) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs552452349). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 550 of the ASNS protein (p.Arg550His). This variant is present in population databases (rs552452349, gnomAD 0.008%). This missense change has been observed in individuals with asparagine synthetase deficiency (PMID: 29405484, 32255274). ClinVar contains an entry for this variant (Variation ID: 800534). 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 ASNS protein function. This variant disrupts the p.Arg550 amino acid residue in ASNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24139043, 27522229). 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.

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1649G>A (p.R550H) alteration is located in exon 14 (coding exon 11) of the ASNS gene. This alteration results from a G to A substitution at nucleotide position 1649, causing the arginine (R) at amino acid position 550 to be replaced by a histidine (H). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the ASNS c.1649G>A alteration was observed in 0.001% (3/282746) of total alleles studied, with a frequency of 0.008% (2/24964) in the African subpopulation. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in multiple affected individuals, including in the homozygous state as well as in trans with a second alteration in ASNS; commonly reported features include microcephaly, developmental delay, seizures, spasticity, and abnormal brain MRI including atrophy and simplified gyral pattern (Faoucher, 2017; Galada, 2018; Wang, 2020). Biochemical features showed low plasma asparagine level in two patients and low CSF asparagine level in one patient reported by Faoucher, et al. (2017)._x000D_ _x000D_ Additionally, an alteration at the same codon, c.1648C>T (p.R550C), has been observed in affected individuals, including in the homozygous state in two affected siblings with severe developmental delay, progressive microcephaly, axial hypotonia with appendicular hypertonia, hyperreflexia, hyperekplexia, and decreased cerebral volume and simplified gyri on brain MRI (Ruzzo, 2013) and in trans with a second alteration in two siblings with severe epileptic encephalopathy, gyral simplification, and microcephaly (Zillhardt, 2016). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R550 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.R550H alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.