ClinVar Genomic variation as it relates to human health

NM_000487.5(ARSA):c.1232C>T(T411I) is classified as likely pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 18832844, 22798296, 21265945, 19154224, 10459747 and 7909527. Classification of NM_000487.5(ARSA):c.1232C>T(T411I) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: ARSA c.1232C>T (p.Thr411Ile) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. Two computational tools predict a significant impact on normal splicing, suggesting the variant strengthens a cryptic 3' acceptor site in the exon 27 bp away from the canonical splice site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in both normal and aberrant transcript with a 27 bp deletion from the usual exon 8 splice acceptor site. The variant was absent in 238866 control chromosomes (gnomAD). c.1232C>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Hasegawa_1994, Fukutani_1999, Suzuki_2008, Miura_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in 10%-<30% of normal ARSA activity (Hasegawa_1994). The following publications have been ascertained in the context of this evaluation (PMID: 7909527, 18832844, 22798296, 10459747). ClinVar contains an entry for this variant (Variation ID: 3087). Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 8 (PMID: 7909527). Experimental studies have shown that this missense change affects ARSA function (PMID: 7909527). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSA protein function. ClinVar contains an entry for this variant (Variation ID: 3087). This variant is also known as p.Thr409Ile. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7909527, 18832844, 19154224, 21265945, 22798296). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 411 of the ARSA protein (p.Thr411Ile). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.