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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 11, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001855074.6

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

NM_000487.6(ARSA):c.854+1G>T

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>T
HGVS:
  • NC_000022.11:g.50626590C>A
  • NG_009260.2:g.6590G>T
  • NG_146552.1:g.361C>A
  • NM_000487.6:c.854+1G>TMANE SELECT
  • NM_001085425.3:c.854+1G>T
  • NM_001085426.3:c.854+1G>T
  • NM_001085427.3:c.854+1G>T
  • NM_001085428.3:c.596+1G>T
  • NM_001362782.2:c.596+1G>T
  • NC_000022.10:g.51065018C>A
  • NM_000487.5:c.854+1G>T
Links:
dbSNP: rs886041911
NCBI 1000 Genomes Browser:
rs886041911
Molecular consequence:
  • NM_000487.6:c.854+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085425.3:c.854+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085426.3:c.854+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085427.3:c.854+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001085428.3:c.596+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001362782.2:c.596+1G>T - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002235685Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 11, 2020) 		germlineclinical testing

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

Help

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002235685.3

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

Description

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with exon skipping, which introduces a premature termination codon (PMID: 7833949). The resulting mRNA is expected to undergo nonsense-mediated decay. Disruption of this splice site has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7833949). ClinVar contains an entry for this variant (Variation ID: 280764). This sequence change affects a donor splice site in intron 4 of the ARSA gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

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

Last Updated: Sep 29, 2024