ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.1283C>T (p.Pro428Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000487.6(ARSA):c.1283C>T (p.Pro428Leu)
Variation ID: 3052 Accession: VCV000003052.74
- Type and length
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single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50625392 (GRCh38) [ NCBI UCSC ] 22: 51063820 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 8, 2024 Sep 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000487.6:c.1283C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Pro428Leu missense NM_001085425.3:c.1283C>T NP_001078894.2:p.Pro428Leu missense NM_001085426.3:c.1283C>T NP_001078895.2:p.Pro428Leu missense NM_001085427.3:c.1283C>T NP_001078896.2:p.Pro428Leu missense NM_001085428.3:c.1025C>T NP_001078897.1:p.Pro342Leu missense NM_001362782.2:c.1025C>T NP_001349711.1:p.Pro342Leu missense NC_000022.11:g.50625392G>A NC_000022.10:g.51063820G>A NG_009260.2:g.7788C>T - Protein change
- P428L, P342L
- Other names
- P426L
- Canonical SPDI
- NC_000022.11:50625391:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
- As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes to disease. [submitted by Gelb Laboratory, University of Washington]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00037
The Genome Aggregation Database (gnomAD) 0.00037
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD), exomes 0.00039
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ARSA | - | - |
GRCh38 GRCh37 |
1254 | 1422 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
|
Jan 1, 1997 | RCV000003195.13 | |
Arylsulfatase a, allele a
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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1997 | RCV000003196.13 |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1997 | RCV000003197.13 | |
Pathogenic (14) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2024 | RCV000020314.55 | |
Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2024 | RCV000392246.40 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 1, 2019 | RCV001251909.10 | |
ARSA-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Aug 7, 2024 | RCV004755702.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 11, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593419.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
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Pathogenic
(Aug 06, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110801.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 10
Sex: mixed
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163453.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
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Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193818.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000487.5(ARSA):c.1283C>T(P428L) is classified as pathogenic in the context of metachromatic leukodystrophy. Please note that the P428L variant is associated with the juvenile or adult form … (more)
NM_000487.5(ARSA):c.1283C>T(P428L) is classified as pathogenic in the context of metachromatic leukodystrophy. Please note that the P428L variant is associated with the juvenile or adult form of this disease. Sources cited for classification include the following: PMID 8095918, 20339381, 11777924 and 1670590. Classification of NM_000487.5(ARSA):c.1283C>T(P428L) 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. (less)
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Pathogenic
(Mar 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329084.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 19, 2017 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as P426L due to the use of alternate nomenclature; … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as P426L due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 7866401, 8095918, 18786133, 1670590, 26462614, 29413149, 29915382, 31186049, 31980526) (less)
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Pathogenic
(Aug 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581156.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PS3_MOD, PM3, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: male
|
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767236.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2) for a recessive condition (105 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in multiple individuals with metachromatic leukodystrophy (ClinVar, PMID: 26462614). (SP) 0903 - This variant has limited evidence for segregation with disease (PMID: 26462614). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. It was shown to result in deficiency of protein octamerisation, lack of stability in lysosomes and reduced enzymatic activity (PMID: 11777924). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627138.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 428 of the ARSA protein (p.Pro428Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 428 of the ARSA protein (p.Pro428Leu). This variant is present in population databases (rs28940893, gnomAD 0.08%). This missense change has been observed in individuals with metachromatic leukodystrophy (MLD) (PMID: 1670590, 9090526, 9096767, 11941485, 26462614). ClinVar contains an entry for this variant (Variation ID: 3052). 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: 11777924, 11941485). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429405.5
First in ClinVar: Aug 17, 2020 Last updated: Apr 15, 2024 |
Clinical Features:
Spastic paraparesis (present) , Memory impairment (present) , Leukodystrophy (present) , Abnormal central sensory function (present)
Sex: female
|
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Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245875.23
First in ClinVar: May 09, 2020 Last updated: Oct 08, 2024 |
Comment:
ARSA: PM3:Very Strong, PM1, PM2, PS3:Supporting
Number of individuals with the variant: 7
|
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Pathogenic
(Mar 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696807.2
First in ClinVar: Jan 06, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: ARSA c.1283C>T (p.Pro428Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging … (more)
Variant summary: ARSA c.1283C>T (p.Pro428Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 268786 control chromosomes. c.1283C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Polten_1991, Barth_1993). These data indicate that the variant is very likely to be associated with disease. A functional study, Polten_1991, found the enzymatic activity to be <10% of normal activity. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 30, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001476147.2
First in ClinVar: Jan 26, 2021 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been previously referred to as c.1277C>T (p.Pro426Leu) in … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been previously referred to as c.1277C>T (p.Pro426Leu) in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant prevents complete protein polymerization, leading to reduced stability, and complete proteolysis by lysosomal cysteine proteinases (PMID 11777924). 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. (less)
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Pathogenic
(Nov 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893596.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021443.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Sep 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005328382.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
Detected in trans with another pathogenic variant
Clinical Features:
Atypical behavior (present) , Parkinsonian disorder (present) , Apraxia (present) , Leukodystrophy (present) , Reduced impulse control (present)
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Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, JUVENILE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023353.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site mutation, referred to as 'allele I' (607574.0003) and a C-to-T transition, resulting in a pro426-to-leu (P426L) substitution, referred to as 'allele A.' To test the functional consequence of this mutation, Polten et al. (1991) introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection. Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5). Polten et al. (1991) determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization. Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2. Neither allele was found in 18 of the 68 patients. In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, Polten et al. (1991) found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease. Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances. Heterozygosity for allele I (with the other allele unknown) was usually associated with late infantile disease, and heterozygosity for allele A with later onset of the disease. Draghia et al. (1997), cited reports stating that the P426L mutation and a splice site mutation (607574.0003) have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). (less)
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Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
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ARYLSULFATASE A, ALLELE A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023354.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site mutation, referred to as 'allele I' (607574.0003) and a C-to-T transition, resulting in a pro426-to-leu (P426L) substitution, referred to as 'allele A.' To test the functional consequence of this mutation, Polten et al. (1991) introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection. Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5). Polten et al. (1991) determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization. Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2. Neither allele was found in 18 of the 68 patients. In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, Polten et al. (1991) found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease. Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances. Heterozygosity for allele I (with the other allele unknown) was usually associated with late infantile disease, and heterozygosity for allele A with later onset of the disease. Draghia et al. (1997), cited reports stating that the P426L mutation and a splice site mutation (607574.0003) have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). (less)
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Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, ADULT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023355.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found compound heterozygosity for 2 mutations in the ARSA gene: a splice site mutation, referred to as 'allele I' (607574.0003) and a C-to-T transition, resulting in a pro426-to-leu (P426L) substitution, referred to as 'allele A.' To test the functional consequence of this mutation, Polten et al. (1991) introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection. Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5). Polten et al. (1991) determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization. Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2. Neither allele was found in 18 of the 68 patients. In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, Polten et al. (1991) found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease. Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances. Heterozygosity for allele I (with the other allele unknown) was usually associated with late infantile disease, and heterozygosity for allele A with later onset of the disease. Draghia et al. (1997), cited reports stating that the P426L mutation and a splice site mutation (607574.0003) have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). (less)
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Uncertain significance
(Jan 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427655.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741563.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922599.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929214.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951884.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jan 04, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081638.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
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Pathogenic
(Aug 07, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ARSA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005351163.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ARSA c.1283C>T variant is predicted to result in the amino acid substitution p.Pro428Leu. In the homozygous and compound heterozygous states, this variant has been … (more)
The ARSA c.1283C>T variant is predicted to result in the amino acid substitution p.Pro428Leu. In the homozygous and compound heterozygous states, this variant has been documented in numerous patients with metachromatic leukodystrophy (Cesani et al. 2016. PubMed ID: 26462614). It is one of the most common causative variants in the ARSA gene, and functional studies support its pathogenicity (Polten et al. 1991. PubMed ID: 1670590, legacy nomenclature p.Pro426Leu). This variant is classified as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807480.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966409.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036616.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040689.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: in vitro
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: not applicable
Allele origin:
not applicable
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Gelb Laboratory, University of Washington
Accession: SCV005046747.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment on evidence:
0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken … (more)
0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken as mild, and >13% is taken as benign, see PMID: 37480112 (less)
Method: tandem mass spectrometry used to measure enymatic activity
Result:
0.04% of wild type enzymatic activity
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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Method citation(s):
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Gelb Laboratory, University of Washington
Accession: SCV005046747.1
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Comment:
As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes to disease.
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Arylsulfatase A Deficiency. | Adam MP | - | 2024 | PMID: 20301309 |
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix. | Trinidad M | Genome biology | 2023 | PMID: 37480112 |
Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients. | Beerepoot S | Neurogenetics | 2020 | PMID: 32632536 |
Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. | Wolf NI | Annals of clinical and translational neurology | 2020 | PMID: 31967741 |
Phenotypic variation between siblings with Metachromatic Leukodystrophy. | Elgün S | Orphanet journal of rare diseases | 2019 | PMID: 31186049 |
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. | Sun M | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29915382 |
Recon3D enables a three-dimensional view of gene variation in human metabolism. | Brunk E | Nature biotechnology | 2018 | PMID: 29457794 |
Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells. | Böhringer J | Human mutation | 2017 | PMID: 28762252 |
Impact of genetic variation on three dimensional structure and function of proteins. | Bhattacharya R | PloS one | 2017 | PMID: 28296894 |
Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. | Sessa M | Lancet (London, England) | 2016 | PMID: 27289174 |
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. | Cesani M | Human mutation | 2016 | PMID: 26462614 |
Biochemical and Genetic Analysis of Seven Korean Individuals With Suspected Metachromatic Leukodystrophy. | Han M | Annals of laboratory medicine | 2015 | PMID: 26131420 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Molecular bases of metachromatic leukodystrophy in Polish patients. | Lugowska A | Journal of human genetics | 2010 | PMID: 20339381 |
Novel mutations associated with metachromatic leukodystrophy: phenotype and expression studies in nine Czech and Slovak patients. | Berná L | American journal of medical genetics. Part A | 2004 | PMID: 15326627 |
Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. | Regis S | Human genetics | 2002 | PMID: 11941485 |
Defective oligomerization of arylsulfatase a as a cause of its instability in lysosomes and metachromatic leukodystrophy. | von Bülow R | The Journal of biological chemistry | 2002 | PMID: 11777924 |
Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. | Berger J | American journal of medical genetics | 1997 | PMID: 9096767 |
Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene. | Draghia R | Human mutation | 1997 | PMID: 9090526 |
Molecular genetics of metachromatic leukodystrophy. | Gieselmann V | Human mutation | 1994 | PMID: 7866401 |
Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. | Barth ML | Human genetics | 1993 | PMID: 8095918 |
An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy. | Gieselmann V | Human genetics | 1991 | PMID: 1671769 |
Molecular basis of different forms of metachromatic leukodystrophy. | Polten A | The New England journal of medicine | 1991 | PMID: 1670590 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA | - | - | - | - |
- | - | - | - | BookShelf: NBK15952986 |
- | - | - | - | BookShelf: NBK16140556 |
- | - | - | - | BookShelf: NBK1670590 |
- | - | - | - | BookShelf: NBK19606494 |
- | - | - | - | BookShelf: NBK9090526 |
- | - | - | - | BookShelf: NBK9096767 |
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Text-mined citations for rs28940893 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.