NM_000487.6(ARSA):c.847G>T (p.Asp283Tyr) AND Metachromatic leukodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000487.6(ARSA):c.847G>T (p.Asp283Tyr)]

NM_000487.6(ARSA):c.847G>T (p.Asp283Tyr)

ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.847G>T (p.Asp283Tyr)
  • NC_000022.11:g.50626598C>A
  • NG_009260.2:g.6582G>T
  • NM_000487.6:c.847G>TMANE SELECT
  • NM_001085425.3:c.847G>T
  • NM_001085426.3:c.847G>T
  • NM_001085427.3:c.847G>T
  • NM_001085428.3:c.589G>T
  • NM_001362782.2:c.589G>T
  • NP_000478.3:p.Asp283Tyr
  • NP_000478.3:p.Asp283Tyr
  • NP_001078894.2:p.Asp283Tyr
  • NP_001078895.2:p.Asp283Tyr
  • NP_001078896.2:p.Asp283Tyr
  • NP_001078897.1:p.Asp197Tyr
  • NP_001349711.1:p.Asp197Tyr
  • NC_000022.10:g.51065026C>A
  • NM_000487.4:c.841G>T
  • NM_000487.5:c.847G>T
  • p.D281Y
Protein change:
UniProtKB/Swiss-Prot: VAR_054189; dbSNP: rs199476386
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000487.6:c.847G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.847G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.847G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.847G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.589G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.589G>T - 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)
SCV000792709Counsylcriteria provided, single submitter
Uncertain significance
(Jul 20, 2017)
unknownclinical testing

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

Citation Link,

SCV001226680Invitaecriteria provided, single submitter
(Sep 9, 2020)
germlineclinical testing

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

Summary from all submissions

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



Metachromatic leucodystrophy: a newly identified mutation in arylsulphatase A, D281Y, found as a compound heterozygote with I179L in an adult onset case.

Halsall DJ, Halligan EP, Elsey TS, Cox TM.

Hum Mutat. 1999 Nov;14(5):447.

PubMed [citation]

Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations.

Dehghan Manshadi M, Kamalidehghan B, Aryani O, Khalili E, Dadgar S, Tondar M, Ahmadipour F, Yong Meng G, Houshmand M.

Ther Clin Risk Manag. 2017;13:725-731. doi: 10.2147/TCRM.S119967.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000792709.1

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

From Invitae, SCV001226680.2

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


This sequence change replaces aspartic acid with tyrosine at codon 283 of the ARSA protein (p.Asp283Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with metachromatic leukodystrophy (PMID: 10533072). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also referred to p.Asp281Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 68151). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp283 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 28670130, 30057904, 31694723), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 16, 2021

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