ClinVar Genomic variation as it relates to human health
NM_000487.6(ARSA):c.465+1G>A
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.465+1G>A
Variation ID: 3051 Accession: VCV000003051.79
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50627165 (GRCh38) [ NCBI UCSC ] 22: 51065593 (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 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000487.6:c.465+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001085425.3:c.465+1G>A splice donor NM_001085426.3:c.465+1G>A splice donor NM_001085427.3:c.465+1G>A splice donor NM_001085428.3:c.207+1G>A splice donor NM_001362782.2:c.207+1G>A splice donor NC_000022.11:g.50627165C>T NC_000022.10:g.51065593C>T NG_009260.2:g.6015G>A NG_146552.1:g.936C>T - Protein change
- Other names
- allele I
- IVS2+1G>A
- IVS2DS, G-A, +1
- Canonical SPDI
- NC_000022.11:50627164: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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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00042
The Genome Aggregation Database (gnomAD) 0.00046
The Genome Aggregation Database (gnomAD), exomes 0.00065
Exome Aggregation Consortium (ExAC) 0.00079
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
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. |
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ARSA | - | - |
GRCh38 GRCh37 |
1131 | 1298 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2001 | RCV000003194.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2001 | RCV000003192.9 | |
Pathogenic (22) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000020319.51 | |
Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000335617.37 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 1, 2019 | RCV001251910.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2022 | RCV001267384.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 13, 2021 | RCV001778645.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2022 | RCV002251862.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2023 | RCV003934795.1 |
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
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
(Sep 30, 2020)
|
criteria provided, single submitter
Method: research
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Cologne University
Accession: SCV001441231.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523090.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PVS1, PM3
Clinical Features:
Neurodevelopmental abnormality (present) , Autistic behavior (present)
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922102.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The homozygous c.465+1G>A variant in ARSA was identified by our study in two siblings with metachromatic leukodystrophy. The c.465+1G>A variant in ARSA has been identified … (more)
The homozygous c.465+1G>A variant in ARSA was identified by our study in two siblings with metachromatic leukodystrophy. The c.465+1G>A variant in ARSA has been identified in 60 unrelated individuals with autosomal recessive metachromatic leukodystrophy (PMID: 11456299, PMID: 7825603, PMID: 9600244, PMID: 18786133, PMID: 15952986, PMID: 9096767, PMID: 9090526, PMID: 8455580, PMID: 8095918, PMID: 21167507, PMID: 7815434, PMID: 2574462, PMID: 1670590), but has been identified in 0.1% (140/121592) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338815). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 3051) and has been interpreted as pathogenic by multiple submitters. Of these 60 affected unrelated individuals, 35 were homozygotes (PMID: 7825603, PMID: 18786133, PMID: 15952986, PMID: 8455580, PMID: 8095918, PMID: 21167507, PMID: 7815434, PMID: 2574462, PMID: 1670590), 8 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 9090526, ClinVar ID: 3052; PMID: 9096767, ClinVar ID: 3052, ClinVar ID: 3057; PMID: 18786133, ClinVar Variation ID: 68144, ClinVar Variation ID: 840642, ClinVar Variation ID: 68126), 11 were presumed compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 1670590, PMID: 8095918, ClinVar Variation ID: 3052; PMID: 15952986, ClinVar Variation ID: 3052, ClinVar ID: 3057; PMID: 9600244, ClinVar ID: 3057), and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 9090526, ClinVar Variation ID: 68115; PMID: 18786133, ClinVar Variation ID: 68145; PMID: 11456299, ClinVar Variation ID: 3092), which increases the likelihood that the c.465+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.465+1G>A variant may impact protein function (PMID: 2574462, PMID: 1670590). However, these types of assays may not accurately represent biological function. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ARSA gene is an established disease mechanism in autosomal recessive metachromatic leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive metachromatic leukodystrophy. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS3_Supporting (Richards 2015). (less)
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Pathogenic
(Jun 03, 2022)
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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: SCV002018774.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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: SCV000627142.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 2 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 2 of the ARSA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is present in population databases (rs80338815, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 1670590, 7825603, 9090526, 9600244, 11456299, 18786133, 21167507, 26462614). ClinVar contains an entry for this variant (Variation ID: 3051). 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
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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ARSA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004756654.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The ARSA c.465+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented in both homozygous … (more)
The ARSA c.465+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented in both homozygous and compound heterozygous states as causative for metachromatic leukodystrophy in numerous patients (Polten et al. 1991. PubMed ID: 1670590; legacy nomenclature: c.459+1G>A, or “I allele”; Gort et al. 1999. PubMed ID: 10477432; Beerepoot et al. 2020. PubMed ID: 32632536). Functional studies support the deleterious effect of this variant (Biffi et al. 2008. PubMed ID: 18786133). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in ARSA are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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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: SCV001245879.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
ARSA: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Number of individuals with the variant: 9
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Pathogenic
(Apr 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610089.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(May 21, 2017)
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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: SCV000696808.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The ARSA c.465+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal … (more)
Variant summary: The ARSA c.465+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which has been functionally supported (Zlotogora_1994 and Polten_1991). This variant was found in 88/111568 control chromosomes at a frequency of 0.0007888, which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSA variant (0.0027951). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals diagnosed with late-, juvenile- and adult-onset depending on the second mutation in trans. The variant of interest has been indicated to be a common founder mutation (Zlotogora_1994 and Polten_1991). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 06, 2015)
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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: SCV000110808.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 52
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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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: SCV000893600.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Dec 18, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915006.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ARSA c.465+1G>A variant, also referred to as c.459+1G>A, has been described as one of the most common pathogenic variants for arylsulfatase A deficiency occurring … (more)
The ARSA c.465+1G>A variant, also referred to as c.459+1G>A, has been described as one of the most common pathogenic variants for arylsulfatase A deficiency occurring in the central and western European populations (Fluharty et al. 2006). Across a selection of the available literature, the c.465+1G>A variant has been identified in at least eight homozygotes, 16 compound heterozygotes, and 25 heterozygotes with an uncharacterized second allele, giving an allele frequency ranging from 7.5% to 37% in patients with arylsulfatase A deficiency (Polten et al. 1991; Eto et al. 1993; Draghia et al. 1997; Berger et al. 1997; Lugowska et al. 2005; Biffi et al. 2008; Shukla et al. 2011). Biochemical analyses indicate that the variant is associated with no residual arylsulfatase A activity (Polten et al. 1991). The c.465+1G>A variant is reported at a frequency of 0.00132 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the c.465+1G>A variant is classified as pathogenic for arylsufatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(May 28, 2019)
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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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Mendelics
Accession: SCV001141463.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163457.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
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Pathogenic
(Dec 11, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001194193.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
NM_000487.5(ARSA):c.465+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of metachromatic leukodystrophy and is associated with the infantile form of this disease. Sources cited for … (more)
NM_000487.5(ARSA):c.465+1G>A(aka IVS2+1G>A) is classified as pathogenic in the context of metachromatic leukodystrophy and is associated with the infantile form of this disease. Sources cited for classification include the following: PMID 1670590 and 8095918. Classification of NM_000487.5(ARSA):c.465+1G>A(aka IVS2+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.‚Äã (less)
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440246.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447222.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Developmental regression (present) , Leukodystrophy (present) , Global developmental delay (present)
Sex: female
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Pathogenic
(Aug 10, 2018)
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criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448761.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability (present) , Short stature (present) , Failure to thrive (present) , Behavioral abnormality (present) , Inguinal hernia (present) , Autistic disorder of childhood … (more)
Intellectual disability (present) , Short stature (present) , Failure to thrive (present) , Behavioral abnormality (present) , Inguinal hernia (present) , Autistic disorder of childhood onset (present) , Gait disturbance (present) , Psychosis (present) , Exotropia (present) , Thrombocytopenia (present) , Hypothyroidism (present) , Expressive language delay (present) , Constipation (present) , Attention deficit hyperactivity disorder (present) , Status epilepticus (present) , Seizures (present) , Cerebral atrophy (present) , Bipolar affective disorder (present) , Migraine (present) , Receptive language delay (present) , Chronic obstructive airway disease from birth (present) , Global developmental delay (present) , Feeding difficulties (present) , Inappropriate behavior (present) (less)
Sex: male
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Pathogenic
(Oct 19, 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: SCV001366183.2
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,PS1,PM2.
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Pathogenic
(Mar 12, 2021)
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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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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001519663.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Family history: no
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Pathogenic
(Aug 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency, Arylsulfatase A
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984802.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant is also known in the literature as c.459+1G>A and IVS2+1G>A (PMID: 1670590, 18786133). This variant affects the canonical splice donor site of intron … (more)
This variant is also known in the literature as c.459+1G>A and IVS2+1G>A (PMID: 1670590, 18786133). This variant affects the canonical splice donor site of intron 2 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This alteration has been previously reported as a compound heterozygous change in patients with Arylsulfatase A Deficiency (also known as metachromatic leukodystrophy (MLD)) (PMID: 1670590, 18786133, 21167507, 26462614, 9090526, 11456299, 9600244, 7825603). Functional studies indicated that this variant leads to extremely low enzymatic activity (PMID: 18786133). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.062% (168/271628). It is one of the most common pathogenic variant causing early-onset (late infantile) MLD in individuals of central and western European ancestry (PMID: 1670590). Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.465+1G>A variant is classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001984757.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Sex: female
|
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Pathogenic
(Sep 13, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV002016300.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
|
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Pathogenic
(Nov 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764723.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Sensorimotor neuropathy (present) , Cerebellar ataxia (present) , Global developmental delay (present) , Nystagmus (present) , Developmental regression (present)
|
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Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767655.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with metachromatic leukodystrophy (MIM#250100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Exact protein consequence is unknown, however analysis of patient cells showed no residual protein (PMID: 1670590). (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (168 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Another canonical splice site variant (c.465+2T>A) has moderate previous evidence for pathogenicity, and has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in many unrelated individuals with metachromatic leukodystrophy (ClinVar, PMID: 28923328). (SP) 1001 - Strong functional evidence supporting abnormal protein function, where homozygous patient fibroblasts had no residual protein (PMID: 1670590). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Nov 17, 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: SCV000329083.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Associated with no detectable arylsulfatase A activity (Gomez-Ospina et al. 2017); Canonical splice site variant in a gene for which loss-of-function is a known mechanism … (more)
Associated with no detectable arylsulfatase A activity (Gomez-Ospina et al. 2017); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Previously reported as c.459+1G>A due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 8095918, 25525159, 1670590, 18786133, 21167507, 7815434, 9600244, 11456299, 7825603, 9090526, 28923328, 20301309, 32632536, 31589614, 31418856, 31186049, 31980526, 33385934) (less)
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Pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
paternal
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026369.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PVS1, PP5, PS3
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Metachromatic leukodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046724.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
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Pathogenic
(Apr 01, 2022)
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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: SCV000801471.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
PP4, PM2, PM3, PS4_moderate, PVS1
Number of individuals with the variant: 3
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Pathogenic
(Jun 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445565.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.465+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the ARSA gene. Alterations that disrupt the … (more)
The c.465+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the ARSA gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This alteration (also known as c.459+1G>A) is one of the most common disease-causing mutations in patients with metachromatic leukodystrophy. In the homozygous state, this mutation is associated with the late-infantile form of disease whereas in the compound heterozygote state, its been associated with a less severe presentation (Comabella, 2001; Cesani, 2016; Draghia, 1997; Heinisch, 1995; Polten, 1991). This nucleotide position is highly conserved in available vertebrate species. Patients homozygous for this alteration were found to have extremely low ARSA enzyme activity in their peripheral mononuclear blood cells (Biffi, 2008). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jul 01, 2001)
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no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, ADULT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023352.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 positions from the published sequence for the ARSA gene. Two of the substitutions represented functionally silent changes; only the loss of a splice donor site in allele I was considered to be relevant to metachromatic leukodystrophy. Specifically, a G-to-A transition destroyed the splice donor site of exon 2 by changing the classic exon-intron boundary consensus sequence from AGgt to AGat. In all 6 instances of homozygosity for allele I, Polten et al. (1991) reported that the clinical picture was that of the late infantile form of metachromatic leukodystrophy. Heinisch et al. (1995) found this mutation in homozygous state in 3 separate Arab families living in the Jerusalem area. Draghia et al. (1997), who referred to this mutation as 459+1G-A, cited reports stating that it, and the P426L mutation (607574.0004), have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). Comabella et al. (2001) reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for this mutation and a 1223C-T transition resulting in a thr408-to-ile (T408I; 607574.0045) substitution in the ARSA gene. The mutations segregated independently; the unaffected father was a carrier for this mutation and 2 daughters from the proband's second marriage were each carriers for 1 or the other of the mutations. Noting that homozygosity for this mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. In an Italian patient with juvenile-onset metachromatic leukodystrophy, Gomez-Lira et al. (1998) identified compound heterozygosity for the 459+1G-A and the I179S (607574.0008) mutations in the ARSA gene. (less)
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Pathogenic
(Jul 01, 2001)
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no assertion criteria provided
Method: literature only
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METACHROMATIC LEUKODYSTROPHY, JUVENILE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023350.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018 |
Comment on evidence:
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 … (more)
In a patient with juvenile-onset metachromatic leukodystrophy (250100), Polten et al. (1991) found 2 different metachromatic leukodystrophy alleles. One, designated allele I, differed in 3 positions from the published sequence for the ARSA gene. Two of the substitutions represented functionally silent changes; only the loss of a splice donor site in allele I was considered to be relevant to metachromatic leukodystrophy. Specifically, a G-to-A transition destroyed the splice donor site of exon 2 by changing the classic exon-intron boundary consensus sequence from AGgt to AGat. In all 6 instances of homozygosity for allele I, Polten et al. (1991) reported that the clinical picture was that of the late infantile form of metachromatic leukodystrophy. Heinisch et al. (1995) found this mutation in homozygous state in 3 separate Arab families living in the Jerusalem area. Draghia et al. (1997), who referred to this mutation as 459+1G-A, cited reports stating that it, and the P426L mutation (607574.0004), have the highest frequency in MLD, each accounting for 25% of mutant alleles among Caucasian patients (Polten et al., 1991; Barth et al., 1993). The remaining 50% of alleles are very heterogeneous, most of them being found in only 1 or 2 patients (Gieselmann et al., 1994). Comabella et al. (2001) reported a consanguineous Spanish family in which a proband and her daughter had atypical adult-onset metachromatic leukodystrophy presenting as isolated peripheral neuropathy. Electrophysiologic studies were consistent with a chronic acquired demyelinating polyneuropathy. Both patients were compound heterozygotes for this mutation and a 1223C-T transition resulting in a thr408-to-ile (T408I; 607574.0045) substitution in the ARSA gene. The mutations segregated independently; the unaffected father was a carrier for this mutation and 2 daughters from the proband's second marriage were each carriers for 1 or the other of the mutations. Noting that homozygosity for this mutation results in severe infantile disease, the authors concluded that the T408I mutation has a relatively mild effect. In an Italian patient with juvenile-onset metachromatic leukodystrophy, Gomez-Lira et al. (1998) identified compound heterozygosity for the 459+1G-A and the I179S (607574.0008) mutations in the ARSA gene. (less)
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Uncertain significance
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
unknown
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427656.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
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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: SCV001462391.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800523.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741313.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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: SCV001926691.1 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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972269.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Metachromatic leukodystrophy
Affected status: yes
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV001423421.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 05-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 05-17-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (disease) (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Memory impairment (present) … (more)
Myopia (disease) (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Memory impairment (present) , Depressivity (present) , Delusions (present) , Short attention span (present) , Oral herpes (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-05-17
Testing laboratory interpretation: Pathogenic
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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: SCV000040694.3
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 |
---|---|---|---|---|
Arylsulfatase A Deficiency. | Adam MP | - | 2024 | PMID: 20301309 |
Mutation Frequency of Three Neurodegenerative Lysosomal Storage Diseases: From Screening to Treatment? | Duarte AJ | Archives of medical research | 2017 | PMID: 28923328 |
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. | Cesani M | Human mutation | 2016 | PMID: 26462614 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
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 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland. | Ługowska A | Clinical genetics | 2005 | PMID: 15952986 |
Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family. | Comabella M | Annals of neurology | 2001 | PMID: 11456299 |
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 |
Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation. | Gomez-Lira M | Human genetics | 1998 | PMID: 9600244 |
Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. | Berger J | American journal of medical genetics | 1997 | PMID: 9096767 |
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 |
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 |
Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. | Heinisch U | American journal of human genetics | 1995 | PMID: 7825603 |
Molecular genetics of metachromatic leukodystrophy. | Gieselmann V | Human mutation | 1994 | PMID: 7866401 |
A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy. | Zlotogora J | Journal of medical genetics | 1994 | PMID: 7815434 |
Molecular characteristics in Japanese patients with lipidosis: novel mutations in metachromatic leukodystrophy and Gaucher disease. | Eto Y | Molecular and cellular biochemistry | 1993 | PMID: 8455580 |
Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. | Barth ML | Human genetics | 1993 | PMID: 8095918 |
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 |
Molecular basis of different forms of metachromatic leukodystrophy. | Polten A | The New England journal of medicine | 1991 | PMID: 1670590 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA | - | - | - | - |
- | - | - | - | BookShelf: NBK15952986 |
- | - | - | - | BookShelf: NBK16140556 |
- | - | - | - | BookShelf: NBK1670590 |
- | - | - | - | BookShelf: NBK19606494 |
- | - | - | - | BookShelf: NBK8455580 |
- | - | - | - | BookShelf: NBK9090526 |
- | - | - | - | BookShelf: NBK9096767 |
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Text-mined citations for rs80338815 ...
HelpRecord last updated May 01, 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.