ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.1150G>A (p.Glu384Lys)
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.1150G>A (p.Glu384Lys)
Variation ID: 3084 Accession: VCV000003084.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50625639 (GRCh38) [ NCBI UCSC ] 22: 51064067 (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 Jun 28, 2015 Jun 2, 2024 Dec 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.1150G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Glu384Lys missense NM_001085425.3:c.1150G>A NP_001078894.2:p.Glu384Lys missense NM_001085426.3:c.1150G>A NP_001078895.2:p.Glu384Lys missense NM_001085427.3:c.1150G>A NP_001078896.2:p.Glu384Lys missense NM_001085428.3:c.892G>A NP_001078897.1:p.Glu298Lys missense NM_001362782.2:c.892G>A NP_001349711.1:p.Glu298Lys missense NC_000022.11:g.50625639C>T NC_000022.10:g.51064067C>T NG_009260.2:g.7541G>A - Protein change
- E384K, E298K
- Other names
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E382K
- Canonical SPDI
- NC_000022.11:50625638:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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functionally_normal; Sequence Ontology [ SO:0002219]As described in PMID: 37480112, ARSA enzymatic activity >13% of wild type is taken as benign and likely does not contribute 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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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
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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 |
1256 | 1424 |
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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Sep 1, 1994 | RCV000003230.11 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2023 | RCV000078936.24 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2021 | RCV000723624.15 |
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
(Apr 18, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110796.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(May 28, 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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Mendelics
Accession: SCV001141461.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
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Likely pathogenic
(Aug 18, 2017)
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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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Counsyl
Accession: SCV000793445.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Likely pathogenic
(Dec 06, 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: SCV002073989.2
First in ClinVar: Feb 13, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15375602, 7906588, 32632536) (less)
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Pathogenic
(Dec 27, 2023)
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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: SCV000752522.7
First in ClinVar: Jun 28, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 384 of the ARSA protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 384 of the ARSA protein (p.Glu384Lys). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs74315479, gnomAD 0.007%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7906588, 15375602, 19021637, 20339381, 26462614). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1144G>A or E382K. ClinVar contains an entry for this variant (Variation ID: 3084). 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 not expected to disrupt ARSA protein function with a negative predictive value of 95%. Studies have shown that this missense change results in exon 7 skipping and introduces a new termination codon (PMID: 15375602). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 1994)
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no assertion criteria provided
Method: literature only
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ARYLSULFATASE A PSEUDODEFICIENCY, INTERMEDIATE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023388.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016 |
Comment on evidence:
In Caucasian patients with intermediate arylsulfatase A pseudodeficiency (250100), Barth et al. (1994) identified a G-to-A substitution of the ARSA gene changing a glutamic acid … (more)
In Caucasian patients with intermediate arylsulfatase A pseudodeficiency (250100), Barth et al. (1994) identified a G-to-A substitution of the ARSA gene changing a glutamic acid to lysine at position 382 in exon 7. (less)
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Likely 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: SCV001809416.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(May 06, 2021)
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no assertion criteria provided
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002081642.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926821.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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: SCV005046783.1
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:
70.22% 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
Help
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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functionally_normal
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Method citation(s):
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Gelb Laboratory, University of Washington
Accession: SCV005046783.1
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Comment:
As described in PMID: 37480112, ARSA enzymatic activity >13% of wild type is taken as benign and likely does not contribute 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 |
Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry. | Hong X | Analytical chemistry | 2020 | PMID: 31922725 |
Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy. | van Rappard DF | Neurology | 2016 | PMID: 27261095 |
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 |
Molecular bases of metachromatic leukodystrophy in Polish patients. | Lugowska A | Journal of human genetics | 2010 | PMID: 20339381 |
Molecular and clinical consequences of novel mutations in the arylsulfatase A gene. | Ługowska A | Clinical genetics | 2009 | PMID: 19021637 |
ASA E382K disrupts a potential exonic splicing enhancer and causes exon skipping, but missense mutations in ASA are not associated with ESEs. | Shotelersuk V | International journal of molecular medicine | 2004 | PMID: 15375602 |
Two novel mutations in the arylsulfatase A gene associated with juvenile (R390Q) and adult onset (H397Y) metachromatic leukodystrophy. | Coulter-Mackie MB | Human mutation | 1998 | PMID: 9452102 |
Molecular genetics of metachromatic leukodystrophy. | Gieselmann V | Human mutation | 1994 | PMID: 7866401 |
Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. | Barth ML | Journal of medical genetics | 1994 | PMID: 7815433 |
Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients. | Barth ML | Human molecular genetics | 1993 | PMID: 7906588 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA | - | - | - | - |
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Text-mined citations for rs74315479 ...
HelpRecord last updated Nov 25, 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.