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

dbSNP: rs74315483

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169048	SCV002185606	pathogenic	Metachromatic leukodystrophy	2024-09-17	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs74315483, gnomAD 0.0009%). 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 also known as E253K. ClinVar contains an entry for this variant (Variation ID: 3091). 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%. Experimental studies have shown that this missense change affects ARSA function (PMID: 11941485). For these reasons, this variant has been classified as Pathogenic.
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
Gelb Laboratory, University of Washington	RCV000169048	SCV005046553	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro