ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.763G>A (p.Glu255Lys)

dbSNP: rs74315483
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169048 SCV000220207 likely pathogenic Metachromatic leukodystrophy 2014-03-30 criteria provided, single submitter literature only
GeneDx RCV000364541 SCV000329854 pathogenic not provided 2022-11-18 criteria provided, single submitter clinical testing Published functional demonstrate residual enzyme activity of 6.7% compared to controls, supporting a damaging effect (Regis et al., 2002); 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: 18786133, 23559313, 26462614, 31589614, 18693274, 11941485)
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000169048 SCV001367112 pathogenic Metachromatic leukodystrophy 2019-09-08 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PS3_M,PM3,PP3,PP4.
Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine RCV000169048 SCV001832551 pathogenic Metachromatic leukodystrophy 2021-07-01 criteria provided, single submitter clinical testing
Invitae RCV000169048 SCV002185606 pathogenic Metachromatic leukodystrophy 2023-05-27 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 11941485). 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. ClinVar contains an entry for this variant (Variation ID: 3091). This variant is also known as E253K. This missense change has been observed in individual(s) with late infantile metachromatic leukodystrophy (PMID: 11941485, 18786133). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs74315483, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 255 of the ARSA protein (p.Glu255Lys).
OMIM RCV000003237 SCV000023395 pathogenic Metachromatic leukodystrophy, late infantile form 2002-04-01 no assertion criteria provided literature only
Natera, Inc. RCV000169048 SCV002081660 pathogenic Metachromatic leukodystrophy 2021-02-21 no assertion criteria provided clinical testing

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