NM_000487.6(ARSA):c.160C>G (p.Leu54Val) AND Metachromatic leukodystrophy

Clinical significance:Likely pathogenic (Last evaluated: Aug 27, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000487.6(ARSA):c.160C>G (p.Leu54Val)]

NM_000487.6(ARSA):c.160C>G (p.Leu54Val)

ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.160C>G (p.Leu54Val)
  • NC_000022.11:g.50627620G>C
  • NG_009260.2:g.5560C>G
  • NM_000487.6:c.160C>GMANE SELECT
  • NM_001085425.3:c.160C>G
  • NM_001085426.3:c.160C>G
  • NM_001085427.3:c.160C>G
  • NM_001085428.3:c.-34-214C>G
  • NM_001362782.2:c.-34-214C>G
  • NP_000478.3:p.Leu54Val
  • NP_001078894.2:p.Leu54Val
  • NP_001078895.2:p.Leu54Val
  • NP_001078896.2:p.Leu54Val
  • NC_000022.10:g.51066048G>C
Protein change:
Molecular consequence:
  • NM_001085428.3:c.-34-214C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001362782.2:c.-34-214C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000487.6:c.160C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.160C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.160C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.160C>G - missense variant - [Sequence Ontology: SO:0001583]


Metachromatic leukodystrophy (MLD)
Metachromatic leukoencephalopathy; Sulfatide lipidosis; Cerebral sclerosis diffuse metachromatic form; See all synonyms [MedGen]
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)
SCV001574439Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 27, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Novel mutations in the arylsulfatase A gene in eight Italian families with metachromatic leukodystrophy.

Bertelli M, Gallo S, Buda A, Cecchin S, Fabbri A, Lapucci C, Andrighetto G, Sidoti V, Lorusso L, Pandolfo M.

J Clin Neurosci. 2006 May;13(4):443-8.

PubMed [citation]

Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy.

Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Naldini L, Comi G, Sessa M, Biffi A.

Hum Mutat. 2009 Oct;30(10):E936-45. doi: 10.1002/humu.21093.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001574439.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


This sequence change replaces leucine with valine at codon 54 of the ARSA protein (p.Leu54Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Leu54 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16678723, 19606494). 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.

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

Last Updated: Oct 7, 2021

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