rs74315457

Positions:

• chr22-50626976-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 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 (★★).

• 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:23 O:3
• Conservation: PhyloP100: 6.90

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a strand (size 2) in uniprot entity ARSA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50626976-A-C is Pathogenic according to our data. Variant chr22-50626976-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626976-A-C is described in Lovd as [Pathogenic]. Variant chr22-50626976-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.542T>G	p.Ile181Ser	missense_variant	3/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.542T>G	p.Ile181Ser	missense_variant	3/8	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

GnomAD3 exomes AF: 0.000234 AC: 58 AN: 247648 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134626

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000344

Gnomad4 NFE exome AF: 0.000216

Gnomad4 OTH exome AF: 0.000133

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000306 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:23 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:12 Other:3

not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 03, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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). 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 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine	Jul 01, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 01, 2018	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. -

not provided Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 06, 2024	PP3, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 13, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	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) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ARSA: PM3:Very Strong, PM2, PS3:Supporting -

Metachromatic leukodystrophy, juvenile type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2002

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

Metachromatic leukodystrophy, adult type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315457; hg19: chr22-51065404;