Submissions for variant NM_000487.6(ARSA):c.1150G>A (p.Glu384Lys)

gnomAD frequency: 0.00001  dbSNP: rs74315479

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723624	SCV000110796	pathogenic	not provided	2013-04-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000078936	SCV000752522	pathogenic	Metachromatic leukodystrophy	2024-09-16	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 384 of the ARSA protein (p.Glu384Lys). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs74315479, gnomAD 0.007%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7906588, 15375602, 19021637, 20339381, 26462614). 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 c.1144G>A or E382K. ClinVar contains an entry for this variant (Variation ID: 3084). 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 not expected to disrupt ARSA protein function with a negative predictive value of 95%. Studies have shown that this missense change results in exon 7 skipping and introduces a new termination codon (PMID: 15375602). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000078936	SCV000793445	likely pathogenic	Metachromatic leukodystrophy	2017-08-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000078936	SCV001141461	pathogenic	Metachromatic leukodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000723624	SCV002073989	likely pathogenic	not provided	2024-11-18	criteria provided, single submitter	clinical testing	RNA studies demonstrate a damaging effect: skipping of exon 7 (PMID: 15375602); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7906588, 32632536, 37212343, 31922725, 37480112, 36993451, 15375602, 38564053)
OMIM	RCV000003230	SCV000023388	pathogenic	ARYLSULFATASE A PSEUDODEFICIENCY, INTERMEDIATE	1994-09-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000723624	SCV001809416	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000723624	SCV001926821	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000078936	SCV002081642	pathogenic	Metachromatic leukodystrophy	2021-05-06	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000078936	SCV005046783	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro