ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.293C>T (p.Ser98Phe)
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.293C>T (p.Ser98Phe)
Variation ID: 3054 Accession: VCV000003054.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50627338 (GRCh38) [ NCBI UCSC ] 22: 51065766 (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 Apr 4, 2013 May 12, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.293C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Ser98Phe missense NM_001085425.3:c.293C>T NP_001078894.2:p.Ser98Phe missense NM_001085426.3:c.293C>T NP_001078895.2:p.Ser98Phe missense NM_001085427.3:c.293C>T NP_001078896.2:p.Ser98Phe missense NM_001085428.3:c.35C>T NP_001078897.1:p.Ser12Phe missense NM_001362782.2:c.35C>T NP_001349711.1:p.Ser12Phe missense NC_000022.11:g.50627338G>A NC_000022.10:g.51065766G>A NG_009260.2:g.5842C>T - Protein change
- S98F
- Other names
- S96F
- Canonical SPDI
- NC_000022.11:50627337: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- Comment on variant
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 |
1132 | 1299 |
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
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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Dec 1, 1989 | RCV000003199.10 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000020317.22 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Oct 14, 2019 | RCV000723374.23 |
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
(Aug 05, 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: SCV001821473.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: ARSA c.293C>T (p.Ser98Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ARSA c.293C>T (p.Ser98Phe) results in a non-conservative amino acid change in 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 208510 control chromosomes. c.293C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (example, Gieselmann_1991, Rafi_2003, van Rappard_2016, Beerepoot_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in-vitro (example, Gieselmann_1991). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 01, 2017)
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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: SCV001245881.20
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 08, 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: SCV000110804.5
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Oct 14, 2019)
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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: SCV001825197.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Published functional studies demonstrate loss of enzyme activity (Gieselmann et al., 1991); Not observed at a significant frequency in large population cohorts (Lek et al., … (more)
Published functional studies demonstrate loss of enzyme activity (Gieselmann et al., 1991); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 1678251, 12809637, 32632536, 7649558, 16546179) (less)
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Likely pathogenic
(Dec 09, 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: SCV000220940.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Apr 21, 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: SCV002781876.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 13, 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: SCV001223293.3
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 98 of the ARSA protein (p.Ser98Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 98 of the ARSA protein (p.Ser98Phe). This variant is present in population databases (rs74315456, gnomAD 0.007%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1678251, 12809637, 22993277, 23701968). This variant is also known as c.287C>T, p.Ser96Phe. ClinVar contains an entry for this variant (Variation ID: 3054). 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: 1678251). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 1989)
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no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023357.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In a patient with the late infantile form of metachromatic leukodystrophy (250100), Gieselmann et al. (1991) found homozygosity for the mutations characteristic of the arylsulfatase … (more)
In a patient with the late infantile form of metachromatic leukodystrophy (250100), Gieselmann et al. (1991) found homozygosity for the mutations characteristic of the arylsulfatase A pseudodeficiency allele but, in addition, a C-to-T transition in exon 2 causing a substitution of phenylalanine for serine-96. Gieselmann et al. (1991) pointed out the necessity for care in not overlooking a mutation causing severe deficiency associated with the changes of pseudodeficiency. This can be a serious problem since homozygous pseudodeficiency is present in 1 to 2% of the population. (less)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740349.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958314.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV001807962.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918284.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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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: SCV001927583.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(Oct 13, 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: SCV002083906.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040692.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 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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Arylsulfatase A Deficiency. | Adam MP | - | 2024 | PMID: 20301309 |
Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients. | Beerepoot S | Neurogenetics | 2020 | PMID: 32632536 |
Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy. | van Rappard DF | Neurology | 2016 | PMID: 27261095 |
Apolipoprotein E genotype and LRP1 polymorphisms in patients with different clinical types of metachromatic leukodystrophy. | Ługowska A | Gene | 2013 | PMID: 23701968 |
Cerebral gray and white matter changes and clinical course in metachromatic leukodystrophy. | Groeschel S | Neurology | 2012 | PMID: 22993277 |
Understanding mutations and protein stability through tripeptides. | Anishetty S | FEBS letters | 2006 | PMID: 16546179 |
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 |
Metachromatic leukodystrophy: a 12-bp deletion in exon 2 of the arylsulfatase A gene in a late infantile variant. | Luyten JA | Human genetics | 1995 | PMID: 7649558 |
Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. | Gieselmann V | American journal of human genetics | 1991 | PMID: 1678251 |
Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site. | Gieselmann V | Proceedings of the National Academy of Sciences of the United States of America | 1989 | PMID: 2574462 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA | - | - | - | - |
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Text-mined citations for rs74315456 ...
HelpRecord last updated May 19, 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.
NCBI staff reviewed the sequence information reported in PubMed 1678251 to determine the location of this allele on current reference sequence.
NM_000487.5:c.293C>T was incorrectly defined as insertion and reported as "NM_000487.6:c.293_294insT" from 2019-09-08 to 2022-07-27.