rs80338815
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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. 3/3 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
NM_000487.6 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) 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;
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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ARSA | NM_000487.6 | c.465+1G>A | splice_donor_variant | ENST00000216124.10 | NP_000478.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ARSA | ENST00000216124.10 | c.465+1G>A | splice_donor_variant | 1 | NM_000487.6 | ENSP00000216124 | P1 |
Frequencies
GnomAD3 genomes 0.000427 AC: 65AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000645 AC: 155AN: 240294Hom.: 0 AF XY: 0.000662 AC XY: 87AN XY: 131390
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GnomAD4 exome AF: 0.000856 AC: 1247AN: 1457140Hom.: 0 Cov.: 33 AF XY: 0.000839 AC XY: 608AN XY: 724272
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GnomAD4 genome 0.000427 AC: 65AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32AN XY: 74336
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:39Uncertain:1Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:21Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 19, 2024 | PVS1, PS3_Moderate, PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 03, 2022 | - - |
| 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). - |
| 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 | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Aug 10, 2018 | - - |
| 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 | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | Institute of Human Genetics, Cologne University | Sep 30, 2020 | - - |
| 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 | Mendelics | May 28, 2019 | - - |
| 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, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Mar 12, 2021 | - - |
| 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 - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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 | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| 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 | 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 | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
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, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 06, 2015 | - - |
| 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, 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, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 01, 2022 | PP4, PM2, PM3, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ARSA: PM3:Very Strong, PVS1, PM2, PS3:Supporting - |
Metachromatic leukodystrophy, adult type Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2001 | - - |
| Pathogenic, criteria provided, single submitter | not provided | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
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. - |
ARSA-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | 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. - |
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 - |
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 | - - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at