ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1468T>C (p.Cys490Arg)

dbSNP: rs755974448
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001916305 SCV002180660 likely pathogenic Metachromatic leukodystrophy 2024-04-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 490 of the ARSA protein (p.Cys490Arg). 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 individual(s) with metachromatic leukodystrophy (PMID: 12809637, 31186049). This variant is also known as T1462C, C488R and c.1469T>C, p.C490R. ClinVar contains an entry for this variant (Variation ID: 1410148). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 28762252). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003395277 SCV004119220 likely pathogenic ARSA-related disorder 2023-01-26 criteria provided, single submitter clinical testing The ARSA c.1468T>C variant is predicted to result in the amino acid substitution p.Cys490Arg. This variant is alternatively referred to as p.Cys488Arg using Legacy nomenclature. This variant has been reported in individuals with metachromatic leukodystrophy (Table 2, Family 10, Rafi et al. 2003. PubMed ID: 12809637; Table 2, Coulter-Mackie. 2003. PubMed ID: 12809638; Table S3, Böhringer et al. 2017. PubMed ID: 28762252; Table 1, Elgün et al. 2019. PubMed ID: 31186049 ). In vitro experimental studies suggest this variant leads to reduced ARSA activity (Figure 5, Böhringer et al. 2017. PubMed ID: 28762252). This variant is reported in 0.00094% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-51063635-A-G). This variant is interpreted as likely pathogenic.

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