ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.938G>A (p.Arg313Gln)
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.938G>A (p.Arg313Gln)
Variation ID: 68165 Accession: VCV000068165.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50626195 (GRCh38) [ NCBI UCSC ] 22: 51064623 (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 Jul 15, 2024 Apr 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.938G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Arg313Gln missense NM_001085425.3:c.938G>A NP_001078894.2:p.Arg313Gln missense NM_001085426.3:c.938G>A NP_001078895.2:p.Arg313Gln missense NM_001085427.3:c.938G>A NP_001078896.2:p.Arg313Gln missense NM_001085428.3:c.680G>A NP_001078897.1:p.Arg227Gln missense NM_001362782.2:c.680G>A NP_001349711.1:p.Arg227Gln missense NC_000022.11:g.50626195C>T NC_000022.10:g.51064623C>T NG_009260.2:g.6985G>A - Protein change
- R313Q, R227Q
- Other names
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- Canonical SPDI
- NC_000022.11:50626194:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
- As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes to disease. [submitted by Gelb Laboratory, University of Washington]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 16, 2020 | RCV000058997.7 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 2, 2024 | RCV000984245.11 |
Submissions - Germline
Classification
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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
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 02, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922684.2
First in ClinVar: May 13, 2023 Last updated: Jul 15, 2024 |
Comment:
Variant summary: ARSA c.938G>A (p.Arg313Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging … (more)
Variant summary: ARSA c.938G>A (p.Arg313Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241990 control chromosomes. c.938G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (e.g. Barth_1995, Biffi_2008, Shukla_2011, Fumagalli_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no direct experimental evidence demonstrating an impact on protein function has been reported, although cells from homozygous or compound heterozygous patients showed little or no detectible ASA enzymatic activity (e.g. Biffi_2008, Shukla_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21167507, 7581401, 18786133, 33855715). ClinVar contains an entry for this variant (Variation ID: 68165). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 29, 2016)
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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: SCV000521136.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The R313Q variant in the ARSA gene, also known as R311Q using alternate nomenclature, has been reported previously in association with late-infantile metachromatic leukodystrophy in … (more)
The R313Q variant in the ARSA gene, also known as R311Q using alternate nomenclature, has been reported previously in association with late-infantile metachromatic leukodystrophy in two siblings who were homozygous for R313Q (Shukla et al., 2011; Liaw et al., 2015) and in an affected individual who was heterozygous for R313Q as well as heterozygous for a second pathogenic variant in the ARSA gene (Biffi et al., 2008). The R313Q variant has also been reported in an individual with juvenile metachromatic leukodystrophy who was heterozygous for R313Q without an identified second pathogenic variant but who was also heterozygous for an ARSA pseudodeficiency allele (Barth et al., 1995). The R313Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R313Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at this same residue (R313P) as well as in nearby residues (G310V, G310D, G311S, E314D, A316T, A316D) have been reported in the Human Gene Mutation Database in association with metachromatic leukodystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R313Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Pathogenic
(Jul 16, 2020)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715400.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_Moderate, PM2, PP4, PP3
Number of individuals with the variant: 1
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Pathogenic
(-)
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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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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV003803630.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The missense variant p.R313Q in ARSA (NM_000487.6) has been observed to be homozygous in individuals affected with metachromatic leukodystrophy (Shukla P et al; Gonorazky HD … (more)
The missense variant p.R313Q in ARSA (NM_000487.6) has been observed to be homozygous in individuals affected with metachromatic leukodystrophy (Shukla P et al; Gonorazky HD et al). Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions, indicating that the residue is functionally important(Cesani M et al). This variant was found in ClinVar (Variant 68165) with a classification of Pathogenic/Likely Pathogenic. The p.R313Q variant is observed in 1/29,832 (0.0034%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools are contradictory in their predictions (SIFT-Tolerated, Polyphen- Damaging) and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Global developmental delay (present) , Developmental regression (present) , Spasticity (present)
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Pathogenic
(Jan 08, 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: SCV001588979.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the ARSA protein (p.Arg313Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the ARSA protein (p.Arg313Gln). This variant is present in population databases (rs199476382, gnomAD 0.003%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 21167507, 28667691). This variant is also known as Arg311Gln. ClinVar contains an entry for this variant (Variation ID: 68165). 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.Arg313 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 26462614), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 13, 2018)
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no assertion criteria provided
Method: clinical testing
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132338.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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: SCV000090518.1
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: SCV005046509.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment on evidence:
0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken … (more)
0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken as mild, and >13% is taken as benign, see PMID: 37480112 (less)
Method: tandem mass spectrometry used to measure enymatic activity
Result:
0.10% 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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loss_of_function_variant
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Method citation(s):
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Gelb Laboratory, University of Washington
Accession: SCV005046509.1
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Comment:
As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes to disease.
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Correction to: Three novel variants in the arylsulfatase A (ARSA) gene in patients with metachromatic leukodystrophy (MLD). | Hettiarachchi D | BMC research notes | 2020 | PMID: 31969187 |
Three novel variants in the arylsulfatase A (ARSA) gene in patients with metachromatic leukodystrophy (MLD). | Hettiarachchi D | BMC research notes | 2019 | PMID: 31694723 |
Subacute demyelinating peripheral neuropathy as a novel presentation of late infantile metachromatic leukodystrophy. | Gonorazky HD | Muscle & nerve | 2017 | PMID: 28667691 |
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. | Cesani M | Human mutation | 2016 | PMID: 26462614 |
Late infantile metachromatic leukodystrophy: Clinical manifestations of five Taiwanese patients and Genetic features in Asia. | Liaw HR | Orphanet journal of rare diseases | 2015 | PMID: 26553228 |
Molecular and structural analysis of metachromatic leukodystrophy patients in Indian population. | Shukla P | Journal of the neurological sciences | 2011 | PMID: 21167507 |
Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. | Biffi A | Clinical genetics | 2008 | PMID: 18786133 |
Understanding mutations and protein stability through tripeptides. | Anishetty S | FEBS letters | 2006 | PMID: 16546179 |
Identification of seven novel mutations associated with metachromatic leukodystrophy. | Barth ML | Human mutation | 1995 | PMID: 7581401 |
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Text-mined citations for rs199476382 ...
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.