NM_000487.6(ARSA):c.1450G>C (p.Asp484His) AND Metachromatic leukodystrophy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 14, 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:: RCV001934300.6

Allele description [Variation Report for NM_000487.6(ARSA):c.1450G>C (p.Asp484His)]

NM_000487.6(ARSA):c.1450G>C (p.Asp484His)

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.1450G>C (p.Asp484His)

HGVS:

NC_000022.11:g.50625225C>G
NG_009260.2:g.7955G>C
NM_000487.5:c.1450G>C
NM_000487.6:c.1450G>CMANE SELECT
NM_001085425.3:c.1450G>C
NM_001085426.3:c.1450G>C
NM_001085427.3:c.1450G>C
NM_001085428.3:c.1192G>C
NM_001362782.2:c.1192G>C
NP_000478.3:p.Asp484His
NP_001078894.2:p.Asp484His
NP_001078895.2:p.Asp484His
NP_001078896.2:p.Asp484His
NP_001078897.1:p.Asp398His
NP_001349711.1:p.Asp398His
NC_000022.10:g.51063653C>G

Protein change:

D398H

Links:

dbSNP: rs749061034

NCBI 1000 Genomes Browser:

rs749061034

Molecular consequence:

NM_000487.6:c.1450G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.1450G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.1450G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.1450G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.1192G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.1192G>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054] - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002207810	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 14, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005046800	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002207810

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 14, 2021)

germline

clinical testing

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

SCV005046800

Gelb Laboratory, University of Washington

no classification provided

not provided

not applicable

in vitro

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in 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, SCV002207810.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces aspartic acid with histidine at codon 484 of the ARSA protein (p.Asp484His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs749061034, ExAC 0.005%). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. 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. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Gelb Laboratory, University of Washington, SCV005046800.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in 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]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	not provided	assert pathogenicity		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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