Submissions for variant NM_000487.6(ARSA):c.542T>G (p.Ile181Ser)

gnomAD frequency: 0.00029  dbSNP: rs74315457

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657846	SCV000228890	pathogenic	not provided	2015-02-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020320	SCV000627144	pathogenic	Metachromatic leukodystrophy	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 181 of the ARSA protein (p.Ile181Ser). This variant is present in population databases (rs74315457, gnomAD 0.05%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1684088, 9096767, 12081727, 26462614, 26890752). It has also been observed to segregate with disease in related individuals. This variant is also known as c.536T>G, p.Ile179Ser. ClinVar contains an entry for this variant (Variation ID: 3057). 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: 1684088, 9600244). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020320	SCV000696809	pathogenic	Metachromatic leukodystrophy	2017-03-19	criteria provided, single submitter	clinical testing	Variant summary: The ARSA c.542T>G (p.Ile181Ser) variant located in the alkaline phosphatase-like domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 26/116786 (1/4492), which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant of 1/357. Multiple publications have cited the variant in affected individuals predominantly as compound heterozygotes and indicated to cause late-juvenile/adult onset MLD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx	RCV000657846	SCV000779603	pathogenic	not provided	2021-05-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically, I181S results in approximately 5% residual arylsulfatase A activity, compared to wildtype (Fluharty et al., 1991); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12081727, 31684987, 20301309, 9600244, 26462614, 28762252, 26890752, 18786133, 21896413, 30083785, 31186049, 31262576, 18693274, 31980526, 1684088, 9096767, 32632536, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000020320	SCV000893599	pathogenic	Metachromatic leukodystrophy	2024-04-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000020320	SCV000915004	pathogenic	Metachromatic leukodystrophy	2018-11-01	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ARSA c.542T>G (p.Ile181Ser) missense variant, also reported as p.Ile179Ser, has been identified in 24 individuals with arylsulfatase A deficiency, or metachromatic leukodystrophy, including in a compound heterozygous state in 11 individuals and in a heterozygous state in 13 individuals (Fluharty et al. 1991; Berger et al. 1997; Gomez-Lira et al. 1998; Lugowska et al. 2005). Testing methodology in these studies typically assessed for common variants and lacked comprehensive analysis of the gene for rarer variants, which might explain the presence of the p.Ile181Ser variant in a heterozygous state. Segregation of the variant with the disease was shown in one study. The p.Ile181Ser variant was absent from at least 50 controls and is reported at a frequency of 0.000474 in the European (non-Finnish) population of the Genome Aggregation Database. Functional assays in cultured baby hamster kidney cells demonstrated the p.Ile181Ser variant had approximately 5% activity as compared to wild type (Fluharty et al. 1991). It is suggested that the p.Ile181Ser variant is associated with a late-onset phenotype, including juvenile-onset or adult-onset types (Berger et al. 1997; Lugowska et al. 2005). Based on the collective evidence, the p.Ile181Ser variant is classified as a pathogenic variant for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Genetics, Inc.	RCV000020320	SCV001194033	pathogenic	Metachromatic leukodystrophy	2019-12-04	criteria provided, single submitter	clinical testing	NM_000487.5(ARSA):c.542T>G(I181S) is classified as pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 23701968. Classification of NM_000487.5(ARSA):c.542T>G(I181S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000657846	SCV001245878	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	ARSA: PM3:Very Strong, PM2, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000020320	SCV001369704	pathogenic	Metachromatic leukodystrophy	2018-10-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000020320	SCV001440127	pathogenic	Metachromatic leukodystrophy	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Ambry Genetics	RCV001267385	SCV001445566	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000657846	SCV001447975	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657846	SCV001715402	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	PP3, PS3, PS4
Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine	RCV000020320	SCV001837608	pathogenic	Metachromatic leukodystrophy	2021-07-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000657846	SCV001880043	pathogenic	not provided	2021-01-13	criteria provided, single submitter	clinical testing	This variant is one of the most common variants associated with autosomal recessive metachromatic leukodystrophy in the European population (PMID 15952986, 9096767), therefore The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. This variant is also referred to as c.536T>G (p.Ile179Ser) in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to significantly reduce arylsulfatase A activity (PMID 1684088). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Revvity Omics, Revvity	RCV000020320	SCV002021444	likely pathogenic	Metachromatic leukodystrophy	2020-02-27	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000020320	SCV004100644	pathogenic	Metachromatic leukodystrophy		criteria provided, single submitter	clinical testing	The missense variant p.I181S in ARSA (NM_000487.6) has been previously reported in compound heterozygous state (Gomez-Lira et al, 1998; Lugowska et al, 2005). Functional studies reveal a damaging effect (Gomez-Lira et al, 1998 : Fluharty et al 1991). The variant has been submitted to ClinVar as Pathogenic. The variant in ARSA is observed in 9/21520 (0.0418%) alleles from individuals of Finnish background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016). The p.I181S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.542 in ARSA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000020320	SCV005051966	pathogenic	Metachromatic leukodystrophy	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000003202	SCV000023360	pathogenic	Metachromatic leukodystrophy, juvenile type	2002-05-01	no assertion criteria provided	literature only
OMIM	RCV000003203	SCV000023361	pathogenic	Metachromatic leukodystrophy, adult type	2002-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000020320	SCV000040695	not provided	Metachromatic leukodystrophy		no assertion provided	literature only
GenomeConnect, ClinGen	RCV000020320	SCV001338869	not provided	Metachromatic leukodystrophy		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 05-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657846	SCV001741024	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000657846	SCV001931662	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000020320	SCV002081671	pathogenic	Metachromatic leukodystrophy	2018-01-04	no assertion criteria provided	clinical testing
Gelb Laboratory, University of Washington	RCV000020320	SCV005046609	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro