ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.256C>T (p.Arg86Trp)
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.256C>T (p.Arg86Trp)
Variation ID: 68126 Accession: VCV000068126.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50627375 (GRCh38) [ NCBI UCSC ] 22: 51065803 (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 Oct 22, 2013 Jun 2, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.256C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Arg86Trp missense NM_001085425.3:c.256C>T NP_001078894.2:p.Arg86Trp missense NM_001085426.3:c.256C>T NP_001078895.2:p.Arg86Trp missense NM_001085427.3:c.256C>T NP_001078896.2:p.Arg86Trp missense NM_001085428.3:c.-3C>T 5 prime UTR NM_001362782.2:c.-3C>T 5 prime UTR NC_000022.11:g.50627375G>A NC_000022.10:g.51065803G>A NG_009260.2:g.5805C>T - Protein change
- R86W
- Other names
- -
- Canonical SPDI
- NC_000022.11:50627374: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 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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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not provided (1) |
no classification provided
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- | RCV000058956.2 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 15, 2024 | RCV000409776.13 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Feb 19, 2024 | RCV001090098.3 |
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
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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
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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 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
(Dec 22, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002051321.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: ARSA c.256C>T (p.Arg86Trp) 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.256C>T (p.Arg86Trp) 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 was absent in 225598 control chromosomes (gnomAD). The variant, c.256C>T (aka. c250C>T (Arg84Trp)) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (e.g. Biffi_2008, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated about 6% residual activity (Biffi_2008, Cesani_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar, and classified the variant as pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 16, 2021)
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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: SCV002060223.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000487.5(ARSA):c.256C>T(R86W) is a missense variant classified as pathogenic in the context of metachromatic leukodystrophy. R86W has been observed in cases with relevant disease (PMID: 10477432, … (more)
NM_000487.5(ARSA):c.256C>T(R86W) is a missense variant classified as pathogenic in the context of metachromatic leukodystrophy. R86W has been observed in cases with relevant disease (PMID: 10477432, 18786133, 31694723, 26462614, 25965562, 23559313, 16678723, 26131420). Functional assessments of this variant are available in the literature (PMID: 18786133). R86W has been observed in population frequency databases (gnomAD: NFE 0.007%). In summary, NM_000487.5(ARSA):c.256C>T(R86W) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jan 15, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001229305.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 86 of the ARSA protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 86 of the ARSA protein (p.Arg86Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 10477432, 18786133). This variant is also known as c.399C>T, p.R84W. ClinVar contains an entry for this variant (Variation ID: 68126). 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%. This variant disrupts the p.Arg86 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1353340, 12809637, 18693274, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000090477.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013 |
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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: SCV005046667.1
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:
7.86% of wild type enzymatic activity
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Uncertain significance
(Oct 28, 2019)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Frontotemporal dementia
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Accession: SCV001245562.1
First in ClinVar: May 12, 2020 Last updated: May 12, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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
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: SCV005046667.1
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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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Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix. | Trinidad M | Genome biology | 2023 | PMID: 37480112 |
Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients. | Fumagalli F | Journal of inherited metabolic disease | 2021 | PMID: 33855715 |
Three novel variants in the arylsulfatase A (ARSA) gene in patients with metachromatic leukodystrophy (MLD). | Hettiarachchi D | BMC research notes | 2019 | PMID: 31694723 |
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 |
Genotypic characterization of Brazilian patients with infantile and juvenile forms of metachromatic leukodystrophy. | Virgens MY | Gene | 2015 | PMID: 25965562 |
An Italian cohort study identifies four new pathologic mutations in the ARSA gene. | Galla D | Journal of molecular neuroscience : MN | 2013 | PMID: 23559313 |
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 |
Novel mutations in the arylsulfatase A gene in eight Italian families with metachromatic leukodystrophy. | Bertelli M | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2006 | PMID: 16678723 |
Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy. | Rafi MA | Molecular genetics and metabolism | 2003 | PMID: 12809637 |
Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients. | Gort L | Human mutation | 1999 | PMID: 10477432 |
Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. | Kappler J | Annals of neurology | 1992 | PMID: 1353340 |
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Text-mined citations for rs199476352 ...
HelpRecord last updated Sep 29, 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.