NM_000487.6(ARSA):c.1210+1G>A AND Metachromatic leukodystrophy

Clinical significance:Pathogenic (Last evaluated: Jan 23, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000020312.11

Allele description [Variation Report for NM_000487.6(ARSA):c.1210+1G>A]

NM_000487.6(ARSA):c.1210+1G>A

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.1210+1G>A
HGVS:
  • NC_000022.11:g.50625578C>T
  • NG_009260.2:g.7602G>A
  • NM_000487.6:c.1210+1G>AMANE SELECT
  • NM_001085425.3:c.1210+1G>A
  • NM_001085426.3:c.1210+1G>A
  • NM_001085427.3:c.1210+1G>A
  • NM_001085428.3:c.952+1G>A
  • NM_001362782.2:c.952+1G>A
  • NC_000022.10:g.51064006C>T
  • NM_000487.4:c.1204+1G>A
  • NM_000487.5:c.1210+1G>A
Nucleotide change:
IVS7DS, G-A, +1
Links:
OMIM: 607574.0009; dbSNP: rs80338820
NCBI 1000 Genomes Browser:
rs80338820
Molecular consequence:
  • NM_000487.6:c.1210+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085425.3:c.1210+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085426.3:c.1210+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085427.3:c.1210+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085428.3:c.952+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001362782.2:c.952+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Metachromatic leukodystrophy (MLD)
Synonyms:
Metachromatic leukoencephalopathy; Sulfatide lipidosis; Cerebral sclerosis diffuse metachromatic form; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0018868; MedGen: C0023522; Orphanet: 512; OMIM: 250100

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000040687GeneReviewsno assertion criteria providedpathologic
(Aug 25, 2011)
not providedcuration

SCV000627137Invitaecriteria provided, single submitter
Pathogenic
(Aug 25, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001193871Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Nov 11, 2019)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001478805Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 23, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (8)

Details of each submission

From GeneReviews, SCV000040687.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Invitae, SCV000627137.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change affects a donor splice site in the last intron (intron 7) of the ARSA gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs80338820, ExAC 0.002%). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1684088, 19021637, 16110195, Invitae). This variant is also known as c.1204+1G>A and E7S2195 in the literature. ClinVar contains an entry for this variant (Variation ID: 3058). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Myriad Women's Health, Inc., SCV001193871.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478805.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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