ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.937C>T (p.Arg313Ter)
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.937C>T (p.Arg313Ter)
Variation ID: 434394 Accession: VCV000434394.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50626196 (GRCh38) [ NCBI UCSC ] 22: 51064624 (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 Aug 28, 2017 Oct 8, 2024 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.937C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Arg313Ter nonsense NM_001085425.3:c.937C>T NP_001078894.2:p.Arg313Ter nonsense NM_001085426.3:c.937C>T NP_001078895.2:p.Arg313Ter nonsense NM_001085427.3:c.937C>T NP_001078896.2:p.Arg313Ter nonsense NM_001085428.3:c.679C>T NP_001078897.1:p.Arg227Ter nonsense NM_001362782.2:c.679C>T NP_001349711.1:p.Arg227Ter nonsense NC_000022.11:g.50626196G>A NC_000022.10:g.51064624G>A NG_009260.2:g.6984C>T - Protein change
- R313*, R227*
- Other names
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- Canonical SPDI
- NC_000022.11:50626195:G: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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0.00040 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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
Help
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
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2022 | RCV000760416.19 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2023 | RCV000501028.25 |
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
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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
(Nov 02, 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: SCV000593421.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Mar 30, 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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GeneDx
Accession: SCV000890294.3
First in ClinVar: Mar 19, 2019 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24001781, 12809637, 30674982) (less)
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Pathogenic
(Nov 11, 2019)
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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: SCV001361599.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ARSA c.937C>T (p.Arg313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ARSA c.937C>T (p.Arg313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 242628 control chromosomes (gnomAD). c.937C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (Rafi_2003, Luzi_2013). These data indicate that the variant is likely to be associated with disease. These publications also reported decreased enzyme activity and elevated urinary sulfatide excretion in the patients carrying the variant (Rafi_2003, Luzi_2013). Two ClinVar submissions (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
(Dec 28, 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: SCV001221514.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg313*) in the ARSA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg313*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is present in population databases (rs551472773, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809637). This variant is also known as p.Arg311*. ClinVar contains an entry for this variant (Variation ID: 434394). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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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: SCV001369703.2
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: PVS1,PM2,PP5.
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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:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001984758.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Sex: female
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Pathogenic
(Sep 07, 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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Revvity Omics, Revvity
Accession: SCV002016558.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 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: SCV002585942.14
First in ClinVar: Oct 22, 2022 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Jan 02, 2014)
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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: SCV001132333.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Aug 05, 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: SCV002081648.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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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 |
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 |
Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy. | Hess B | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8962139 |
Text-mined citations for rs551472773 ...
HelpRecord last updated Oct 08, 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.