ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.1010A>T (p.Asp337Val)
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.1010A>T (p.Asp337Val)
Variation ID: 3080 Accession: VCV000003080.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50626033 (GRCh38) [ NCBI UCSC ] 22: 51064461 (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 Mar 29, 2015 May 12, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.1010A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Asp337Val missense NM_001085425.3:c.1010A>T NP_001078894.2:p.Asp337Val missense NM_001085426.3:c.1010A>T NP_001078895.2:p.Asp337Val missense NM_001085427.3:c.1010A>T NP_001078896.2:p.Asp337Val missense NM_001085428.3:c.752A>T NP_001078897.1:p.Asp251Val missense NM_001362782.2:c.752A>T NP_001349711.1:p.Asp251Val missense NC_000022.11:g.50626033T>A NC_000022.10:g.51064461T>A NG_009260.2:g.7147A>T - Protein change
- D337V, D251V
- Other names
- D335V
- Canonical SPDI
- NC_000022.11:50626032:T:A
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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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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), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
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 |
1131 | 1298 |
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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Nov 7, 2018 | RCV000003226.7 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2024 | RCV000169024.26 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV000413321.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 13, 2015 | RCV000414806.4 |
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 13, 2015)
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criteria provided, single submitter
Method: clinical testing
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Leukodystrophy
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492921.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Feb 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000593420.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163454.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Likely pathogenic
(Mar 20, 2014)
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criteria provided, single submitter
Method: literature only
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220172.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(May 04, 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: SCV002806807.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 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: SCV000490408.5
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with no functional arylsulfatase A activity (Hess et al., 1996); Not observed at a significant frequency in large … (more)
Published functional studies demonstrate a damaging effect with no functional arylsulfatase A activity (Hess et al., 1996); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14517960, 29915382, 8723680, 20339381, 7866401) (less)
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Pathogenic
(Sep 13, 2022)
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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: SCV002018819.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 12, 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: SCV000836843.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 337 of the ARSA protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 337 of the ARSA protein (p.Asp337Val). This variant is present in population databases (rs74315475, gnomAD 0.008%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7866401, 8723680, 10381328, 14517960, 20339381). 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 Asp335Val. ClinVar contains an entry for this variant (Variation ID: 3080). 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: 8723680). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2023)
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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: SCV002563738.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Comment:
ARSA: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 3
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Pathogenic
(Jan 01, 2016)
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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: SCV001369264.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic.
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Pathogenic
(Aug 24, 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: SCV001360433.2
First in ClinVar: Jun 22, 2020 Last updated: Sep 08, 2021 |
Comment:
Variant summary: ARSA c.1010A>T (p.Asp337Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of … (more)
Variant summary: ARSA c.1010A>T (p.Asp337Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 204330 control chromosomes (gnomAD). c.1010A>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example: Lugowska_2010, Eng_2003, Qu_1999, Hess_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause a complete loss of catalytic activity of the enzyme (Hess_1996). Eight ClinVar submitters (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
(Feb 07, 2018)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000801467.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
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Pathogenic
(Nov 07, 2018)
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no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, SEVERE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023384.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In Caucasian patients with severe metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported an A-to-T substitution of the ARSA gene changing an aspartic acid to … (more)
In Caucasian patients with severe metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported an A-to-T substitution of the ARSA gene changing an aspartic acid to valine at position 335 in exon 6. (less)
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Pathogenic
(Sep 16, 2020)
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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: SCV001462380.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Effects of glycosylation and pH conditions in the dynamics of human arylsulfatase A. | Virgens MY | Journal of biomolecular structure & dynamics | 2014 | PMID: 23581857 |
Molecular bases of metachromatic leukodystrophy in Polish patients. | Lugowska A | Journal of human genetics | 2010 | PMID: 20339381 |
Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD). | Eng B | Human mutation | 2003 | PMID: 14517960 |
Metachromatic leukodystrophy: subtype genotype/phenotype correlations and identification of novel missense mutations (P148L and P191T) causing the juvenile-onset disease. | Qu Y | Molecular genetics and metabolism | 1999 | PMID: 10381328 |
Characterization of two arylsulfatase A missense mutations D335V and T274M causing late infantile metachromatic leukodystrophy. | Hess B | Human mutation | 1996 | PMID: 8723680 |
Molecular genetics of metachromatic leukodystrophy. | Gieselmann V | Human mutation | 1994 | PMID: 7866401 |
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 |
Text-mined citations for rs74315475 ...
HelpRecord last updated May 12, 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.