NM_000487.6(ARSA):c.854+1G>A AND Metachromatic leukodystrophy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 26, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001192373.3

Allele description [Variation Report for NM_000487.6(ARSA):c.854+1G>A]

NM_000487.6(ARSA):c.854+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.854+1G>A
HGVS:
  • NC_000022.11:g.50626590C>T
  • NG_009260.2:g.6590G>A
  • NM_000487.6:c.854+1G>AMANE SELECT
  • NM_001085425.3:c.854+1G>A
  • NM_001085426.3:c.854+1G>A
  • NM_001085427.3:c.854+1G>A
  • NM_001085428.3:c.596+1G>A
  • NM_001362782.2:c.596+1G>A
  • NC_000022.10:g.51065018C>T
  • NM_000487.5:c.854+1G>A
Molecular consequence:
  • NM_000487.6:c.854+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085425.3:c.854+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085426.3:c.854+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085427.3:c.854+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085428.3:c.596+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001362782.2:c.596+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
SCV001360436Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 25, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001381431Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 26, 2019)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Metachromatic leukodystrophy in the Navajo Indian population: a splice site mutation in intron 4 of the arylsulfatase A gene.

Pastor-Soler NM, Rafi MA, Hoffman JD, Hu D, Wenger DA.

Hum Mutat. 1994;4(3):199-207.

PubMed [citation]
PMID:
7833949

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360436.1

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

Description

Variant summary: ARSA c.854+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: Five predict the variant abolishes a 5' splicing donor site. A functional study, Pastor-Soler_1994, supports these predictions and found the variant to cause a deletion of exon 4. The variant was absent in 243414 control chromosomes (gnomAD). c.854+1G>A has been reported in the literature in multiple homozygous individuals affected with Metachromatic Leukodystrophy (Pastor-Soler_1994). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

From Invitae, SCV001381431.2

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

Description

This sequence change affects a donor splice site in intron 4 of the ARSA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ARSA-related conditions. 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. Donor and acceptor splice site variants 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jun 14, 2021

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