ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.736C>T (p.Arg246Cys)
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.736C>T (p.Arg246Cys)
Variation ID: 3073 Accession: VCV000003073.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50626709 (GRCh38) [ NCBI UCSC ] 22: 51065137 (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 Apr 15, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.736C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000478.3:p.Arg246Cys missense NM_001085425.3:c.736C>T NP_001078894.2:p.Arg246Cys missense NM_001085426.3:c.736C>T NP_001078895.2:p.Arg246Cys missense NM_001085427.3:c.736C>T NP_001078896.2:p.Arg246Cys missense NM_001085428.3:c.478C>T NP_001078897.1:p.Arg160Cys missense NM_001362782.2:c.478C>T NP_001349711.1:p.Arg160Cys missense NC_000022.11:g.50626709G>A NC_000022.10:g.51065137G>A NG_009260.2:g.6471C>T - Protein change
- R246C, R160C
- Other names
- R244C
- Canonical SPDI
- NC_000022.11:50626708: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 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 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV000003219.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2022 | RCV003993733.1 |
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
(-)
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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:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048426.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.736C>T (p.Arg246Cys) in ARSA gene has been observed in individuals affected with metachromatic leukodystrophy (Luzi P et.al.,2013). This variant has been reported … (more)
The missense variant c.736C>T (p.Arg246Cys) in ARSA gene has been observed in individuals affected with metachromatic leukodystrophy (Luzi P et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg246Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0007967% is reported in gnomAD. The amino acid Arg at position 246 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg246Cys in ARSA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . (less)
Clinical Features:
Motor delay (present) , Hyperactivity (present) , Hypotonia (present) , Short attention span (present) , Abnormal cerebellum morphology (present)
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Likely pathogenic
(Oct 29, 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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Revvity Omics, Revvity
Accession: SCV002021442.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 23, 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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Invitae
Accession: SCV001222941.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 246 of the ARSA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 246 of the ARSA protein (p.Arg246Cys). This variant is present in population databases (rs74315470, gnomAD 0.002%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 22993277, 24001781, 26462614, 28670130). This variant is also known as p.Arg244Cys. ClinVar contains an entry for this variant (Variation ID: 3073). 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.Arg246 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9090526, 22993277, 25965562, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy, juvenile type
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812597.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in ARSA is predicted to replace arginine with cysteine at codon 246, p.(Arg246Cys) (historically described as c.730C>T p.Arg244Cys). The arginine residue is … (more)
This sequence change in ARSA is predicted to replace arginine with cysteine at codon 246, p.(Arg246Cys) (historically described as c.730C>T p.Arg244Cys). The arginine residue is highly conserved (94/94 vertebrates, UCSC), and is located in the sulfatase domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (2/113,422 alleles) in the European (non-Finnish) population, which is consistent with a recessive disease. This variant has been detected in the homozygous and compound heterozygous state with a second pathogenic allele in multiple individuals with arylsulfatase A (ASA) deficiency. The phenotype was mainly late-infantile or juvenile metachromatic leukodystrophy (PMID: 9090526, 16966551, 19815439, 22993277, 26462614, 36240581). At least one patient with this variant displayed very low ASA activity in leukocytes and abnormally high sulfatide excretion in urine, which is highly specific for ASA deficiency (PMID: 22993277). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Another missense variant (c.737G>A p.Arg246His) in the same codon with a smaller physicochemical difference has been classified as likely pathogenic for ASA deficiency (PMID: 26462614, 9090526, 22993277, 25965562). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM5, PP3, PP4. (less)
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Likely pathogenic
(Jun 19, 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: SCV000220426.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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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
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023377.3
First in ClinVar: Apr 04, 2013 Last updated: May 30, 2018 |
Comment on evidence:
In Caucasian patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at … (more)
In Caucasian patients with metachromatic leukodystrophy (250100), Gieselmann et al. (1994) reported a C-to-T substitution of the ARSA gene changing an arginine to cysteine at position 244 in exon 4. The mutation changes an SstII restriction site. (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: SCV001462384.1
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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Predicting clinical phenotypes of metachromatic leukodystrophy based on the arylsulfatase A activity and the ARSA genotype? - Chances and challenges. | Santhanakumaran V | Molecular genetics and metabolism | 2022 | PMID: 36240581 |
Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations. | Dehghan Manshadi M | Therapeutics and clinical risk management | 2017 | PMID: 28670130 |
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. | Cesani M | Human mutation | 2016 | PMID: 26462614 |
Genotypic characterization of Brazilian patients with infantile and juvenile forms of metachromatic leukodystrophy. | Virgens MY | Gene | 2015 | PMID: 25965562 |
Sixteen novel mutations in the arylsulfatase A gene causing metachromatic leukodystrophy. | Luzi P | Gene | 2013 | PMID: 24001781 |
Cerebral gray and white matter changes and clinical course in metachromatic leukodystrophy. | Groeschel S | Neurology | 2012 | PMID: 22993277 |
Novel patient cell-based HTS assay for identification of small molecules for a lysosomal storage disease. | Geng H | PloS one | 2011 | PMID: 22216298 |
Biochemical profiling to predict disease severity in metachromatic leukodystrophy. | Tan MA | Molecular genetics and metabolism | 2010 | PMID: 19815439 |
Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. | Rauschka H | Neurology | 2006 | PMID: 16966551 |
Understanding mutations and protein stability through tripeptides. | Anishetty S | FEBS letters | 2006 | PMID: 16546179 |
Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene. | Draghia R | Human mutation | 1997 | PMID: 9090526 |
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 |
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Text-mined citations for rs74315470 ...
HelpRecord last updated Apr 20, 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.