Submissions for variant NM_000487.6(ARSA):c.412C>T (p.Pro138Ser)

dbSNP: rs60504011

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854229	SCV002295871	pathogenic	Metachromatic leukodystrophy	2024-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 138 of the ARSA protein (p.Pro138Ser). This variant is present in population databases (rs60504011, gnomAD 0.002%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 10477432). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as P136S. ClinVar contains an entry for this variant (Variation ID: 68131). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. This variant disrupts the p.Pro138 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7860068, 22854541). 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.
GeneDx	RCV000058962	SCV005437440	pathogenic	not provided	2024-06-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on ARSA enzyme activity (PMID: 10477432); 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: 22854541, 10477432, 37480112)
UniProtKB/Swiss-Prot	RCV000058962	SCV000090483	not provided	not provided		no assertion provided	not provided
Gelb Laboratory, University of Washington	RCV001854229	SCV005046643	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro