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NM_000487.6(ARSA):c.1456G>A (p.Ala486Thr) AND Metachromatic leukodystrophy

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Nov 30, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002741051.3

Allele description [Variation Report for NM_000487.6(ARSA):c.1456G>A (p.Ala486Thr)]

NM_000487.6(ARSA):c.1456G>A (p.Ala486Thr)

Gene:
ARSA:arylsulfatase A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q13.33
Genomic location:
Preferred name:
NM_000487.6(ARSA):c.1456G>A (p.Ala486Thr)
HGVS:
  • NC_000022.11:g.50625219C>T
  • NG_009260.2:g.7961G>A
  • NM_000487.5:c.1456G>A
  • NM_000487.6:c.1456G>AMANE SELECT
  • NM_001085425.3:c.1456G>A
  • NM_001085426.3:c.1456G>A
  • NM_001085427.3:c.1456G>A
  • NM_001085428.3:c.1198G>A
  • NM_001362782.2:c.1198G>A
  • NP_000478.3:p.Ala486Thr
  • NP_001078894.2:p.Ala486Thr
  • NP_001078895.2:p.Ala486Thr
  • NP_001078896.2:p.Ala486Thr
  • NP_001078897.1:p.Ala400Thr
  • NP_001349711.1:p.Ala400Thr
  • NC_000022.10:g.51063647C>T
Protein change:
A400T
Molecular consequence:
  • NM_000487.6:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085425.3:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085426.3:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085427.3:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001085428.3:c.1198G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362782.2:c.1198G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functionally_normal [Sequence Ontology: SO:0002219] - Comment(s)

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003017699Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Nov 30, 2021) 		germlineclinical testing

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

SCV005046778Gelb Laboratory, University of Washington
no classification provided
not providednot applicablein vitro

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot applicablenot applicablenot providednot providednot providednot providednot providedin vitro

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.

Trinidad M, Hong X, Froelich S, Daiker J, Sacco J, Nguyen HP, Campagna M, Suhr D, Suhr T, LeBowitz JH, Gelb MH, Clark WT.

Genome Biol. 2023 Jul 21;24(1):172. doi: 10.1186/s13059-023-03001-z.

PubMed [citation]
PMID:
37480112
PMCID:
PMC10360315

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003017699.1

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 486 of the ARSA protein (p.Ala486Thr). This variant is present in population databases (rs777458560, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected 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. 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.

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

From Gelb Laboratory, University of Washington, SCV005046778.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedin vitro PubMed (1)

Description

"0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken as mild, and >13% is taken as benign, see PMID: 37480112"

PubMed [ID: 37480112]

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not applicablenot applicablenot providednot providedassert pathogenicitynot providednot providednot providednot provided

Last Updated: Sep 29, 2024