NM_000487.6(ARSA):c.1269del (p.Ala424fs) AND Metachromatic leukodystrophy

Clinical significance:Likely pathogenic (Last evaluated: Jul 24, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001212980.1

Allele description [Variation Report for NM_000487.6(ARSA):c.1269del (p.Ala424fs)]

NM_000487.6(ARSA):c.1269del (p.Ala424fs)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.1269del (p.Ala424fs)
HGVS:
  • NC_000022.11:g.50625406del
  • NG_009260.2:g.7774del
  • NM_000487.6:c.1269delMANE SELECT
  • NM_001085425.3:c.1269del
  • NM_001085426.3:c.1269del
  • NM_001085427.3:c.1269del
  • NM_001085428.3:c.1011del
  • NM_001362782.2:c.1011del
  • NP_000478.3:p.Ala424fs
  • NP_001078894.2:p.Ala424fs
  • NP_001078895.2:p.Ala424fs
  • NP_001078896.2:p.Ala424fs
  • NP_001078897.1:p.Ala338fs
  • NP_001349711.1:p.Ala338fs
  • NC_000022.10:g.51063834del
  • NM_000487.5:c.1269del
Protein change:
A338fs
Molecular consequence:
  • NM_000487.6:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085425.3:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085426.3:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085427.3:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001085428.3:c.1011del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001362782.2:c.1011del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001384593Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 24, 2019)
germlineclinical testing

PubMed (5)
[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

Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.

Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M.

Hum Genet. 2002 Apr;110(4):351-5. Epub 2002 Mar 8.

PubMed [citation]
PMID:
11941485

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
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001384593.2

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

Description

This sequence change results in a premature translational stop signal in the ARSA gene (p.Ala424Leufs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acids of the ARSA protein. 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. This variant disrupts the p.Pro428 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11941485, 26462614, 9096767, 9090526). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Oct 7, 2021

Support Center