NM_000487.6(ARSA):c.583del (p.Trp195fs) AND Metachromatic leukodystrophy

Clinical significance:Pathogenic (Last evaluated: Jun 6, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV001251199.3

Allele description [Variation Report for NM_000487.6(ARSA):c.583del (p.Trp195fs)]

NM_000487.6(ARSA):c.583del (p.Trp195fs)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.583del (p.Trp195fs)
HGVS:
  • NC_000022.11:g.50626935del
  • NG_009260.2:g.6245del
  • NM_000487.6:c.583delMANE SELECT
  • NM_001085425.3:c.583del
  • NM_001085426.3:c.583del
  • NM_001085427.3:c.583del
  • NM_001085428.3:c.325del
  • NM_001362782.2:c.325del
  • NP_000478.3:p.Trp195fs
  • NP_001078894.2:p.Trp195fs
  • NP_001078895.2:p.Trp195fs
  • NP_001078896.2:p.Trp195fs
  • NP_001078897.1:p.Trp109fs
  • NP_001349711.1:p.Trp109fs
  • NC_000022.10:g.51065363del
  • NM_000487.4:c.577delT
  • NM_000487.5:c.583del
  • NM_000487.5:c.583delT
  • NM_000487.6:c.583delTMANE SELECT
Protein change:
W109fs
Links:
dbSNP: rs398123416
NCBI 1000 Genomes Browser:
rs398123416
Molecular consequence:
  • NM_000487.6:c.583del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085425.3:c.583del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085426.3:c.583del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085427.3:c.583del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085428.3:c.325del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001362782.2:c.325del - frameshift variant - [Sequence Ontology: SO:0001589]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]
Observations:
1

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
SCV001426592Centogene AG - the Rare Disease Companycriteria provided, single submitter
Pathogenicgermlineclinical testing

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

SCV001441275Gene Mapping Laboratory,Hacettepe Universityno assertion criteria providedPathogenicgermlineresearch

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

SCV001592676Invitaecriteria provided, single submitter
Pathogenic
(Jun 6, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing, research
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]
PMID:
32860008
PMCID:
PMC7852664
See all PubMed Citations (7)

Details of each submission

From Centogene AG - the Rare Disease Company, SCV001426592.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Gene Mapping Laboratory,Hacettepe University, SCV001441275.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedresearch PubMed (1)

Description

Clinical features, enzyme activities and urinary sulfatide levels are compatible with metachromatic leukodystrophy

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV001592676.1

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

Description

This sequence change creates a premature translational stop signal (p.Trp195Glyfs*5) in the ARSA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 26462614). ClinVar contains an entry for this variant (Variation ID: 93124). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

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