rs80338815

chr22-50627165-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000487.6(ARSA):c.465+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,609,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: ARSA NM_000487.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:37 U:1 O:2
• Conservation: PhyloP100: 7.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-50627165-C-T is Pathogenic according to our data. Variant chr22-50627165-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50627165-C-T is described in Lovd as [Pathogenic]. Variant chr22-50627165-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.465+1G>A		splice_donor_variant		ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.465+1G>A		splice_donor_variant		1	NM_000487.6	P1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000645 AC: 155 AN: 240294 Hom.: 0 AF XY: 0.000662 AC XY: 87 AN XY: 131390

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.000381

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000856 AC: 1247 AN: 1457140 Hom.: 0 Cov.: 33 AF XY: 0.000839 AC XY: 608 AN XY: 724272

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.000531

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000615

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74336

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000880 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000586 AC: 5

ExAC AF: 0.000735 AC: 89

EpiCase AF: 0.000927

EpiControl AF: 0.00130

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:20 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with metachromatic leukodystrophy (MIM#250100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Exact protein consequence is unknown, however analysis of patient cells showed no residual protein (PMID: 1670590). (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (168 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Another canonical splice site variant (c.465+2T>A) has moderate previous evidence for pathogenicity, and has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in many unrelated individuals with metachromatic leukodystrophy (ClinVar, PMID: 28923328). (SP) 1001 - Strong functional evidence supporting abnormal protein function, where homozygous patient fibroblasts had no residual protein (PMID: 1670590). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 31, 2020	This variant is also known in the literature as c.459+1G>A and IVS2+1G>A (PMID: 1670590, 18786133). This variant affects the canonical splice donor site of intron 2 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This alteration has been previously reported as a compound heterozygous change in patients with Arylsulfatase A Deficiency (also known as metachromatic leukodystrophy (MLD)) (PMID: 1670590, 18786133, 21167507, 26462614, 9090526, 11456299, 9600244, 7825603). Functional studies indicated that this variant leads to extremely low enzymatic activity (PMID: 18786133). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.062% (168/271628). It is one of the most common pathogenic variant causing early-onset (late infantile) MLD in individuals of central and western European ancestry (PMID: 1670590). Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.465+1G>A variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 19, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 11, 2019	NM_000487.5(ARSA):c.465+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of metachromatic leukodystrophy and is associated with the infantile form of this disease. Sources cited for classification include the following: PMID 1670590 and 8095918. Classification of NM_000487.5(ARSA):c.465+1G>A(aka IVS2+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 21, 2017	Variant summary: The ARSA c.465+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which has been functionally supported (Zlotogora_1994 and Polten_1991). This variant was found in 88/111568 control chromosomes at a frequency of 0.0007888, which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant (0.0027951). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals diagnosed with late-, juvenile- and adult-onset depending on the second mutation in trans. The variant of interest has been indicated to be a common founder mutation (Zlotogora_1994 and Polten_1991). 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	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 10, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 12, 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	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Cologne University	Sep 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change affects a donor splice site in intron 2 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is present in population databases (rs80338815, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 1670590, 7825603, 9090526, 9600244, 11456299, 18786133, 21167507, 26462614). ClinVar contains an entry for this variant (Variation ID: 3051). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 18, 2018	The ARSA c.465+1G>A variant, also referred to as c.459+1G>A, has been described as one of the most common pathogenic variants for arylsulfatase A deficiency occurring in the central and western European populations (Fluharty et al. 2006). Across a selection of the available literature, the c.465+1G>A variant has been identified in at least eight homozygotes, 16 compound heterozygotes, and 25 heterozygotes with an uncharacterized second allele, giving an allele frequency ranging from 7.5% to 37% in patients with arylsulfatase A deficiency (Polten et al. 1991; Eto et al. 1993; Draghia et al. 1997; Berger et al. 1997; Lugowska et al. 2005; Biffi et al. 2008; Shukla et al. 2011). Biochemical analyses indicate that the variant is associated with no residual arylsulfatase A activity (Polten et al. 1991). The c.465+1G>A variant is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the c.465+1G>A variant is classified as pathogenic for arylsufatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous c.465+1G>A variant in ARSA was identified by our study in two siblings with metachromatic leukodystrophy. The c.465+1G>A variant in ARSA has been identified in 60 unrelated individuals with autosomal recessive metachromatic leukodystrophy (PMID: 11456299, PMID: 7825603, PMID: 9600244, PMID: 18786133, PMID: 15952986, PMID: 9096767, PMID: 9090526, PMID: 8455580, PMID: 8095918, PMID: 21167507, PMID: 7815434, PMID: 2574462, PMID: 1670590), but has been identified in 0.1% (140/121592) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338815). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 3051) and has been interpreted as pathogenic by multiple submitters. Of these 60 affected unrelated individuals, 35 were homozygotes (PMID: 7825603, PMID: 18786133, PMID: 15952986, PMID: 8455580, PMID: 8095918, PMID: 21167507, PMID: 7815434, PMID: 2574462, PMID: 1670590), 8 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 9090526, ClinVar ID: 3052; PMID: 9096767, ClinVar ID: 3052, ClinVar ID: 3057; PMID: 18786133, ClinVar Variation ID: 68144, ClinVar Variation ID: 840642, ClinVar Variation ID: 68126), 11 were presumed compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 1670590, PMID: 8095918, ClinVar Variation ID: 3052; PMID: 15952986, ClinVar Variation ID: 3052, ClinVar ID: 3057; PMID: 9600244, ClinVar ID: 3057), and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 9090526, ClinVar Variation ID: 68115; PMID: 18786133, ClinVar Variation ID: 68145; PMID: 11456299, ClinVar Variation ID: 3092), which increases the likelihood that the c.465+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.465+1G>A variant may impact protein function (PMID: 2574462, PMID: 1670590). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ARSA gene is an established disease mechanism in autosomal recessive metachromatic leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive metachromatic leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS3_Supporting (Richards 2015). -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 24, 2017	- -
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	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 03, 2023	PVS1, PP5, PS3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ARSA: PM3:Very Strong, PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2019	Associated with no detectable arylsulfatase A activity (Gomez-Ospina et al. 2017); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Previously reported as c.459+1G>A due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 8095918, 25525159, 1670590, 18786133, 21167507, 7815434, 9600244, 11456299, 7825603, 9090526, 28923328, 20301309, 32632536, 31589614, 31418856, 31186049, 31980526, 33385934) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Apr 01, 2022	PP4, PM2, PM3, PS4_moderate, PVS1 -

Metachromatic leukodystrophy, juvenile type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

The c.465+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the ARSA gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This alteration (also known as c.459+1G>A) is one of the most common disease-causing mutations in patients with metachromatic leukodystrophy. In the homozygous state, this mutation is associated with the late-infantile form of disease whereas in the compound heterozygote state, its been associated with a less severe presentation (Comabella, 2001; Cesani, 2016; Draghia, 1997; Heinisch, 1995; Polten, 1991). This nucleotide position is highly conserved in available vertebrate species. Patients homozygous for this alteration were found to have extremely low ARSA enzyme activity in their peripheral mononuclear blood cells (Biffi, 2008). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 14, 2022

ACMG classification criteria: PVS1, PM3 -

ARSA-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2023

The ARSA c.465+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented in both homozygous and compound heterozygous states as causative for metachromatic leukodystrophy in numerous patients (Polten et al. 1991. PubMed ID: 1670590; legacy nomenclature: c.459+1G>A, or “I allele”; Gort et al. 1999. PubMed ID: 10477432; Beerepoot et al. 2020. PubMed ID: 32632536). Functional studies support the deleterious effect of this variant (Biffi et al. 2008. PubMed ID: 18786133). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in ARSA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Sep 13, 2021

- -

Metachromatic leukodystrophy, adult type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	30
Dann	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		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: rs80338815; hg19: chr22-51065593; COSMIC: COSV99049447; COSMIC: COSV99049447;