ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.542T>G (p.Ile181Ser)
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
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NM_000487.6(ARSA):c.542T>G (p.Ile181Ser)
Variation ID: 3057 Accession: VCV000003057.75
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50626976 (GRCh38) [ NCBI UCSC ] 22: 51065404 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 17, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.542T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Ile181Ser missense NM_001085425.3:c.542T>G NP_001078894.2:p.Ile181Ser missense NM_001085426.3:c.542T>G NP_001078895.2:p.Ile181Ser missense NM_001085427.3:c.542T>G NP_001078896.2:p.Ile181Ser missense NM_001085428.3:c.284T>G NP_001078897.1:p.Ile95Ser missense NM_001362782.2:c.284T>G NP_001349711.1:p.Ile95Ser missense NC_000022.11:g.50626976A>C NC_000022.10:g.51065404A>C NG_009260.2:g.6204T>G - Protein change
- I181S, I95S
- Other names
- I179S
- Canonical SPDI
- NC_000022.11:50626975:A:C
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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 4 to <13% of wild type is taken as moderate and may 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.
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Exome Aggregation Consortium (ExAC) 0.00022
The Genome Aggregation Database (gnomAD), exomes 0.00023
The Genome Aggregation Database (gnomAD) 0.00029
- Comment on variant
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 |
1244 | 1411 |
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
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May 1, 2002 | RCV000003202.3 | |
Pathogenic (1) |
no assertion criteria provided
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May 1, 2002 | RCV000003203.3 | |
Pathogenic/Likely pathogenic (15) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000020320.42 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2022 | RCV000657846.37 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2014 | RCV001267385.3 |
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
(Mar 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696809.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 10, 2015)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000228890.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 9
Sex: mixed
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440127.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
Comment:
This variant was identified as compound heterozygous.
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Pathogenic
(Jan 13, 2021)
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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: SCV001880043.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 07, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445566.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian/Polish/French/German/Irish/Scottish
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Pathogenic
(-)
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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:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100644.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Frontotemporal dementia (present) , Muscle weakness (present) , Memory impairment (present) , Atypical behavior (present) , Apraxia (present) , Gait disturbance (present) , Sleep abnormality … (more)
Frontotemporal dementia (present) , Muscle weakness (present) , Memory impairment (present) , Atypical behavior (present) , Apraxia (present) , Gait disturbance (present) , Sleep abnormality (present) , Cerebral cortical atrophy (present) , Parkinsonian disorder (present) (less)
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Likely pathogenic
(Feb 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021444.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245878.22
First in ClinVar: May 09, 2020 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Metachromatic leukodystrophy
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051966.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Nov 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915004.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194033.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447975.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Leukodystrophy (present)
Sex: male
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Pathogenic
(Oct 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369704.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
|
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Pathogenic
(Jul 01, 2021)
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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:
unknown
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Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine
Accession: SCV001837608.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
Clinical Features:
Chorea (present) , Memory impairment (present) , Leukodystrophy (present)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893599.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000779603.4
First in ClinVar: Jul 09, 2018 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000627144.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715402.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024 |
Number of individuals with the variant: 3
|
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Pathogenic
(May 01, 2002)
|
no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, JUVENILE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023360.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3. They designated this mutation E3P799 according to the following scheme: location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence; and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon. Lugowska et al. (2002) pointed out that this mutation, designated I179S in the accepted terminology, had been described in 15 of 130 MLD patients in the literature. All of them were found to have been heterozygous for this mutation. Lugowska et al. (2002) stated that, according to the Hardy-Weinberg law for 2 alleles, 1 homozygote I179S/I179S among 12 late juveniles and adults studied by them should have been found. Thus, they speculated that the residual ARSA activity in an I179S homozygote might be similar to that found in an individual homozygous for the ARSA pseudodeficiency allele (607574.0001) who does not present with clinical symptoms of classic MLD. In 2 Italian patients with metachromatic leukodystrophy, one with adult onset and the other with juvenile onset, Gomez-Lira et al. (1998) identified compound heterozygosity for mutations in the ARSA gene. Both carried the I179S mutation (607574.0008); the patient with juvenile onset had the common 459+1G-A (607574.0003) mutation, and the patient with adult onset had a pro135-to-leu mutation (607574.0042). (less)
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Pathogenic
(May 01, 2002)
|
no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, ADULT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023361.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3. They designated this mutation E3P799 according to the following scheme: location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence; and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon. Lugowska et al. (2002) pointed out that this mutation, designated I179S in the accepted terminology, had been described in 15 of 130 MLD patients in the literature. All of them were found to have been heterozygous for this mutation. Lugowska et al. (2002) stated that, according to the Hardy-Weinberg law for 2 alleles, 1 homozygote I179S/I179S among 12 late juveniles and adults studied by them should have been found. Thus, they speculated that the residual ARSA activity in an I179S homozygote might be similar to that found in an individual homozygous for the ARSA pseudodeficiency allele (607574.0001) who does not present with clinical symptoms of classic MLD. In 2 Italian patients with metachromatic leukodystrophy, one with adult onset and the other with juvenile onset, Gomez-Lira et al. (1998) identified compound heterozygosity for mutations in the ARSA gene. Both carried the I179S mutation (607574.0008); the patient with juvenile onset had the common 459+1G-A (607574.0003) mutation, and the patient with adult onset had a pro135-to-leu mutation (607574.0042). (less)
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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: SCV001741024.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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: SCV002081671.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
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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: SCV001931662.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
paternal
|
GenomeConnect, ClinGen
Accession: SCV001338869.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Myopia (disease) (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Memory impairment (present) … (more)
Myopia (disease) (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Memory impairment (present) , Depressivity (present) , Delusions (present) , Short attention span (present) , Oral herpes (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-05-17
Testing laboratory interpretation: Pathogenic
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not provided
(-)
|
no classification provided
Method: literature only
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040695.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
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not provided
(-)
|
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: SCV005046609.1
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:
4.32% of wild type enzymatic activity
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Germline Functional Evidence
Functional
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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
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A brief description of the result of this method for this variant. |
Submitter
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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
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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: SCV005046609.1
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Comment:
As described in PMID: 37480112, ARSA enzymatic activity of 4 to <13% of wild type is taken as moderate and may 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 |
Association of Age at Onset and First Symptoms With Disease Progression in Patients With Metachromatic Leukodystrophy. | Kehrer C | Neurology | 2021 | PMID: 33046606 |
Comprehensive clinical, biochemical, radiological and genetic analysis of 28 Turkish cases with suspected metachromatic leukodystrophy and their relatives. | Pekgül F | Molecular genetics and metabolism reports | 2020 | PMID: 33335837 |
Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients. | Beerepoot S | Neurogenetics | 2020 | PMID: 32632536 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Phenotypic variation between siblings with Metachromatic Leukodystrophy. | Elgün S | Orphanet journal of rare diseases | 2019 | PMID: 31186049 |
Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells. | Böhringer J | Human mutation | 2017 | PMID: 28762252 |
Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene. | Stoeck K | Journal of Alzheimer's disease : JAD | 2016 | PMID: 26890752 |
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. | Cesani M | Human mutation | 2016 | PMID: 26462614 |
Sixteen novel mutations in the arylsulfatase A gene causing metachromatic leukodystrophy. | Luzi P | Gene | 2013 | PMID: 24001781 |
Apolipoprotein E genotype and LRP1 polymorphisms in patients with different clinical types of metachromatic leukodystrophy. | Ługowska A | Gene | 2013 | PMID: 23701968 |
Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. | Cesani M | Human mutation | 2009 | PMID: 19606494 |
Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. | Biffi A | Clinical genetics | 2008 | PMID: 18786133 |
Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles. | Grossi S | Human mutation | 2008 | PMID: 18693274 |
Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. | Rauschka H | Neurology | 2006 | PMID: 16966551 |
Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland. | Ługowska A | Clinical genetics | 2005 | PMID: 15952986 |
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 |
Investigations of micro-organic brain damage (MOBD) in heterozygotes of metachromatic leukodystrophy. | Tylki-Szymańska A | American journal of medical genetics | 2002 | PMID: 12116203 |
High prevalence of I179S mutation in patients with late-onset metachromatic leukodystrophy. | Lugowska A | Clinical genetics | 2002 | PMID: 12081727 |
Metachromatic leucodystrophy: a newly identified mutation in arylsulphatase A, D281Y, found as a compound heterozygote with I179L in an adult onset case. | Halsall DJ | Human mutation | 1999 | PMID: 10533072 |
Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation. | Gomez-Lira M | Human genetics | 1998 | PMID: 9600244 |
Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. | Berger J | American journal of medical genetics | 1997 | PMID: 9096767 |
Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient. | Fluharty AL | American journal of human genetics | 1991 | PMID: 1684088 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA | - | - | - | - |
- | - | - | - | BookShelf: NBK15952986 |
- | - | - | - | BookShelf: NBK1684088 |
- | - | - | - | BookShelf: NBK19606494 |
- | - | - | - | BookShelf: NBK9096767 |
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Text-mined citations for rs74315457 ...
HelpRecord last updated Jun 17, 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.
NCBI staff reviewed the sequence information reported in PubMed 1684088 to determine the location of this allele on current reference sequence.