NM_000487.6(ARSA):c.825G>T (p.Glu275Asp) AND Metachromatic leukodystrophy

Clinical significance:Uncertain significance (Last evaluated: Jan 23, 2019)

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.825G>T (p.Glu275Asp)]

NM_000487.6(ARSA):c.825G>T (p.Glu275Asp)

ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.825G>T (p.Glu275Asp)
  • NC_000022.11:g.50626620C>A
  • NG_009260.2:g.6560G>T
  • NM_000487.6:c.825G>TMANE SELECT
  • NM_001085425.3:c.825G>T
  • NM_001085426.3:c.825G>T
  • NM_001085427.3:c.825G>T
  • NM_001085428.3:c.567G>T
  • NM_001362782.2:c.567G>T
  • NP_000478.3:p.Glu275Asp
  • NP_001078894.2:p.Glu275Asp
  • NP_001078895.2:p.Glu275Asp
  • NP_001078896.2:p.Glu275Asp
  • NP_001078897.1:p.Glu189Asp
  • NP_001349711.1:p.Glu189Asp
  • NC_000022.10:g.51065048C>A
  • NM_000487.5:c.825G>T
Protein change:
Molecular consequence:
  • NM_000487.6:c.825G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.825G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.825G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.825G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.567G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.567G>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)
SCV001420123Invitaecriteria provided, single submitter
Uncertain significance
(Jan 23, 2019)
germlineclinical testing

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

Summary from all submissions

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



Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV001420123.1

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


This sequence change replaces glutamic acid with aspartic acid at codon 275 of the ARSA protein (p.Glu275Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. 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 disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 30, 2021

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