NM_000487.5(ARSA):c.1210+1G>A is classified as pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 23701968 and 1684088. Classification of NM_000487.5(ARSA):c.1210+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.1210+1G>A
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000487.6(ARSA):c.1210+1G>A
Variation ID: 3058 Accession: VCV000003058.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50625578 (GRCh38) [ NCBI UCSC ] 22: 51064006 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Oct 17, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000487.6:c.1210+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001085425.3:c.1210+1G>A splice donor NM_001085426.3:c.1210+1G>A splice donor NM_001085427.3:c.1210+1G>A splice donor NM_001085428.3:c.952+1G>A splice donor NM_001362782.2:c.952+1G>A splice donor NC_000022.11:g.50625578C>T NC_000022.10:g.51064006C>T NG_009260.2:g.7602G>A - Protein change
- -
- Other names
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IVS7DS, G-A, +1
- Canonical SPDI
- NC_000022.11:50625577:C:T
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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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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| ARSA | - | - |
GRCh38 GRCh37 |
1256 | 1424 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 1991 | RCV000003204.3 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 17, 2022 | RCV000020312.20 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2021 | RCV000723835.26 |
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
(Jun 13, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232062.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Sex: mixed
|
|
|
Pathogenic
(Nov 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193871.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000487.5(ARSA):c.1210+1G>A is classified as pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 23701968 and 1684088. Classification of NM_000487.5(ARSA):c.1210+1G>A … (more)
NM_000487.5(ARSA):c.1210+1G>A is classified as pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 23701968 and 1684088. Classification of NM_000487.5(ARSA):c.1210+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Jan 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001478805.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: ARSA c.1210+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: ARSA c.1210+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250804 control chromosomes. c.1210+1G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy and has been subsequently cited by others (example, Fluherty_1991, Lugowska_2005, Lugowska_2009, Rauschka_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic with some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Oct 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627137.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of … (more)
Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. ClinVar contains an entry for this variant (Variation ID: 3058). This variant is also known as c.1204+1G>A and E7S2195. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 1684088, 16110195, 19021637; Invitae). This variant is present in population databases (rs80338820, gnomAD 0.002%). This sequence change affects a donor splice site in intron 7 of the ARSA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. (less)
|
|
|
Pathogenic
(Mar 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001143056.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more)
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. Predicted to negatively affect a known splice site. (less)
|
|
|
Pathogenic
(Dec 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962458.20
First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Dec 01, 1991)
|
no assertion criteria provided
Method: literature only
|
METACHROMATIC LEUKODYSTROPHY, JUVENILE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023362.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) found compound heterozygosity for a point mutation (see 607574.0008) and for a G-to-A … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Fluharty et al. (1991) found compound heterozygosity for a point mutation (see 607574.0008) and for a G-to-A transition that resulted in an altered splice-recognition sequence between exon 7 and the following intron. The mutation involved nucleotide 2195, the first nucleotide in intron 7. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040687.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: in vitro
|
Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: not applicable
Allele origin:
not applicable
|
Gelb Laboratory, University of Washington
Accession: SCV005046712.1
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% of wild type enzymatic activity
|
Comment:
Comment:
Variant summary: ARSA c.1210+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250804 control chromosomes. c.1210+1G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy and has been subsequently cited by others (example, Fluherty_1991, Lugowska_2005, Lugowska_2009, Rauschka_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic with some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. ClinVar contains an entry for this variant (Variation ID: 3058). This variant is also known as c.1204+1G>A and E7S2195. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 1684088, 16110195, 19021637; Invitae). This variant is present in population databases (rs80338820, gnomAD 0.002%). This sequence change affects a donor splice site in intron 7 of the ARSA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Comment:
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. Predicted to negatively affect a known splice site.
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. |
|---|---|---|---|---|
|
loss_of_function_variant
|
Method citation(s):
|
|
Gelb Laboratory, University of Washington
Accession: SCV005046712.1
|
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.
|
Comment:
NM_000487.5(ARSA):c.1210+1G>A is classified as pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 23701968 and 1684088. Classification of NM_000487.5(ARSA):c.1210+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Variant summary: ARSA c.1210+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250804 control chromosomes. c.1210+1G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy and has been subsequently cited by others (example, Fluherty_1991, Lugowska_2005, Lugowska_2009, Rauschka_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic with some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. ClinVar contains an entry for this variant (Variation ID: 3058). This variant is also known as c.1204+1G>A and E7S2195. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 1684088, 16110195, 19021637; Invitae). This variant is present in population databases (rs80338820, gnomAD 0.002%). This sequence change affects a donor splice site in intron 7 of the ARSA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Comment:
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. Predicted to negatively affect a known splice site.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Arylsulfatase A Deficiency. | Adam MP | - | 2024 | PMID: 20301309 |
| Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix. | Trinidad M | Genome biology | 2023 | PMID: 37480112 |
| Biochemical and Genetic Analysis of Seven Korean Individuals With Suspected Metachromatic Leukodystrophy. | Han M | Annals of laboratory medicine | 2015 | PMID: 26131420 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Apolipoprotein E genotype and LRP1 polymorphisms in patients with different clinical types of metachromatic leukodystrophy. | Ługowska A | Gene | 2013 | PMID: 23701968 |
| Molecular and clinical consequences of novel mutations in the arylsulfatase A gene. | Ługowska A | Clinical genetics | 2009 | PMID: 19021637 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. | Rauschka H | Neurology | 2006 | PMID: 16966551 |
| Homozygote for mutation c.1204 + 1G > A of the ARSA gene presents with a late-infantile form of metachromatic leukodystrophy and a rare MRI white matter lesion type. | Ługowska A | Journal of applied genetics | 2005 | PMID: 16110195 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient. | Fluharty AL | American journal of human genetics | 1991 | PMID: 1684088 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA | - | - | - | - |
| - | - | - | - | BookShelf: NBK15952986 |
| - | - | - | - | BookShelf: NBK1684088 |
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Text-mined citations for rs80338820 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 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.