rs74315457

Variant names:

• chr22-50626976-A-C
• rs74315457
• NM_000487.6:c.542T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PP2 PP3 PP5_Very_Strong

The NM_000487.6(ARSA):​c.542T>G​(p.Ile181Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000197 in 1,612,680 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I181I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 O:2
• Conservation: PhyloP100: 6.90
• Publications: 27 publications found

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ARSA Gene-Disease associations (from GenCC):

• metachromatic leukodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• metachromatic leukodystrophy, juvenile form

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000487.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 159 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.38013 (below the threshold of 3.09). Trascript score misZ: -0.56919 (below the threshold of 3.09). GenCC associations: The gene is linked to metachromatic leukodystrophy, juvenile form, metachromatic leukodystrophy.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, REVEL, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• PP5: Variant 22-50626976-A-C is Pathogenic according to our data. Variant chr22-50626976-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.542T>G	p.Ile181Ser	missense_variant	Exon 3 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.542T>G	p.Ile181Ser	missense_variant	Exon 3 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000234 AC: 58 AN: 247648 AF XY: 0.000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1460562 Hom.: 1 Cov.: 33 AF XY: 0.000191 AC XY: 139 AN XY: 726564

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.000344 AC: 18 AN: 52254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000216 AC: 240 AN: 1111920

Other (OTH) AF: 0.000133 AC: 8 AN: 60368

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:13 Other:2

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3. -

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 28, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 04, 2018

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous. -

Jul 01, 2021

Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 19, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

Feb 27, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:9

May 18, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARSA: PM3:Very Strong, PM2, PS3:Supporting -

Feb 10, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PS3, PS4 -

Metachromatic leukodystrophy, juvenile type Pathogenic:1

May 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Sep 07, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metachromatic leukodystrophy, adult type Pathogenic:1

May 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;T;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;.;.;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Uncertain	0.74	D
PhyloP100		6.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;D;N;D
REVEL	Pathogenic	0.79
Sift	Benign	0.069	T;T;T;D;T
Sift4G	Uncertain	0.058	T;T;T;D;T
Vest4		0.38
MVP		0.95
ClinPred		0.21	T
GERP RS		5.5
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74315457; hg19: chr22-51065404;