NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer) AND Metachromatic leukodystrophy

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 27, 2019)

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:
RCV000078942.7

Allele description [Variation Report for NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer)]

NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer)
HGVS:
  • NC_000022.11:g.50627585del
  • NG_009260.2:g.5595del
  • NM_000487.6:c.195delMANE SELECT
  • NM_001085425.3:c.195del
  • NM_001085426.3:c.195del
  • NM_001085427.3:c.195del
  • NM_001085428.3:c.-34-179del
  • NM_001362782.2:c.-34-179del
  • NP_000478.3:p.Phe64_Tyr65insTer
  • NP_001078894.2:p.Phe64_Tyr65insTer
  • NP_001078895.2:p.Phe64_Tyr65insTer
  • NP_001078896.2:p.Phe64_Tyr65insTer
  • NC_000022.10:g.51066013del
  • NM_000487.5:c.195del
  • NM_000487.5:c.195delC
Links:
dbSNP: rs398123414
NCBI 1000 Genomes Browser:
rs398123414
Molecular consequence:
  • NM_001085428.3:c.-34-179del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001362782.2:c.-34-179del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000487.6:c.195del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085425.3:c.195del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085426.3:c.195del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001085427.3:c.195del - 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
SCV000586685Neurometabolisches Labor,University hospital Tuebingencriteria provided, single submitter
Pathogenic
(May 1, 2017)
unknownresearch

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

SCV000788912Counsylcriteria provided, single submitter
Likely pathogenic
(Dec 23, 2016)
unknownclinical testing

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

Citation Link,

SCV001203142Invitaecriteria provided, single submitter
Pathogenic
(May 27, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedresearch
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sixteen novel mutations in the arylsulfatase A gene causing metachromatic leukodystrophy.

Luzi P, Rafi MA, Rao HZ, Wenger DA.

Gene. 2013 Nov 10;530(2):323-8. doi: 10.1016/j.gene.2013.08.065. Epub 2013 Aug 31.

PubMed [citation]
PMID:
24001781

Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells.

Böhringer J, Santer R, Schumacher N, Gieseke F, Cornils K, Pechan M, Kustermann-Kuhn B, Handgretinger R, Schöls L, Harzer K, Krägeloh-Mann I, Müller I.

Hum Mutat. 2017 Nov;38(11):1511-1520. doi: 10.1002/humu.23306. Epub 2017 Sep 6.

PubMed [citation]
PMID:
28762252
See all PubMed Citations (5)

Details of each submission

From Neurometabolisches Labor,University hospital Tuebingen, SCV000586685.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000788912.1

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

From Invitae, SCV001203142.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Tyr65*) 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 individuals affected with metachromatic leukodystrophy (PMID: 24001781, 28762252). This variant is also known as 189delC, Y63X in the literature. ClinVar contains an entry for this variant (Variation ID: 93121). 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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