ClinVar Genomic variation as it relates to human health

Variant summary: ARSA c.1174C>T (p.Arg392Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251156 control chromosomes (gnomAD). c.1174C>T (also known as c.1168C>T, p.R390W) has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example: Shukula_2011, Liaw_2015, and Mahdieh_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Liaw_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 392 of the ARSA protein (p.Arg392Trp). This variant is present in population databases (rs74315480, gnomAD 0.006%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 21167507, 26462614, 26553228). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg390Trp. ClinVar contains an entry for this variant (Variation ID: 3085). 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 ARSA protein function. This variant disrupts the p.Arg392 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452102, 20339381, 26462614). 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.

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; Also known as p.(R390W); This variant is associated with the following publications: (PMID: 7866401, 30674982, 25965562, 26553228, 21167507, 18693274, 26462614, 23701968, 7581401, 9090526, 20339381, 32632536, 33385934)

The observed missense c.1174C>T(p.Arg392Trp) variant in gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with metachromatic leukodystrophy (Liaw et al., 2015). This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic (multiple submitters). The amino acid Arg at position 392 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg392Trp in ARSA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant disrupts the p.Arg392 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Cesani et al., 2016). Multiple lines of computational evidence (SIFT - Damaging, and MutationTaster - Automatic Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.