NM_000487.6(ARSA):c.925G>T (p.Glu309Ter) AND Metachromatic leukodystrophy

Clinical significance:Likely pathogenic (Last evaluated: Nov 29, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001193048.1

Allele description [Variation Report for NM_000487.6(ARSA):c.925G>T (p.Glu309Ter)]

NM_000487.6(ARSA):c.925G>T (p.Glu309Ter)

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.925G>T (p.Glu309Ter)
HGVS:
  • NC_000022.11:g.50626208C>A
  • NG_009260.2:g.6972G>T
  • NM_000487.6:c.925G>TMANE SELECT
  • NM_001085425.3:c.925G>T
  • NM_001085426.3:c.925G>T
  • NM_001085427.3:c.925G>T
  • NM_001085428.3:c.667G>T
  • NM_001362782.2:c.667G>T
  • NP_000478.3:p.Glu309Ter
  • NP_001078894.2:p.Glu309Ter
  • NP_001078895.2:p.Glu309Ter
  • NP_001078896.2:p.Glu309Ter
  • NP_001078897.1:p.Glu223Ter
  • NP_001349711.1:p.Glu223Ter
  • NC_000022.10:g.51064636C>A
  • NM_000487.5:c.925G>T
Protein change:
E223*
Molecular consequence:
  • NM_000487.6:c.925G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085425.3:c.925G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085426.3:c.925G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085427.3:c.925G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085428.3:c.667G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001362782.2:c.667G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001361597Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Nov 29, 2019)
germlineclinical testing

PubMed (2)
[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

Citations

PubMed

Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles.

Grossi S, Regis S, Rosano C, Corsolini F, Uziel G, Sessa M, Di Rocco M, Parenti G, Deodato F, Leuzzi V, Biancheri R, Filocamo M.

Hum Mutat. 2008 Nov;29(11):E220-30. doi: 10.1002/humu.20851.

PubMed [citation]
PMID:
18693274

Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.

Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A.

Hum Mutat. 2016 Jan;37(1):16-27. doi: 10.1002/humu.22919. Epub 2015 Nov 4. Review.

PubMed [citation]
PMID:
26462614

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361597.1

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

Description

Variant summary: ARSA c.925G>T (p.Glu309X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 246094 control chromosomes (gnomAD). c.925G>T has been reported in the literature in a compound heterozygous individual affected with Metachromatic Leukodystrophy (Grossi_2008). 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 likely pathogenic.

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

Last Updated: Jun 14, 2021

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