NM_000487.6(ARSA):c.764A>C (p.Glu255Ala) AND Metachromatic leukodystrophy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 30, 2023
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:: RCV003502002.2

Allele description [Variation Report for NM_000487.6(ARSA):c.764A>C (p.Glu255Ala)]

NM_000487.6(ARSA):c.764A>C (p.Glu255Ala)

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.764A>C (p.Glu255Ala)

HGVS:

NC_000022.11:g.50626681T>G
NG_009260.2:g.6499A>C
NG_146552.1:g.452T>G
NM_000487.6:c.764A>CMANE SELECT
NM_001085425.3:c.764A>C
NM_001085426.3:c.764A>C
NM_001085427.3:c.764A>C
NM_001085428.3:c.506A>C
NM_001362782.2:c.506A>C
NP_000478.3:p.Glu255Ala
NP_001078894.2:p.Glu255Ala
NP_001078895.2:p.Glu255Ala
NP_001078896.2:p.Glu255Ala
NP_001078897.1:p.Glu169Ala
NP_001349711.1:p.Glu169Ala
NC_000022.10:g.51065109T>G

Protein change:

E169A

Molecular consequence:

NM_000487.6:c.764A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.764A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.764A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.764A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.506A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.506A>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004311949	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11941485, 18786133, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004311949

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 30, 2023)

germline

clinical testing

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

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

Citations

PubMed

Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.

Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M.

Hum Genet. 2002 Apr;110(4):351-5. Epub 2002 Mar 8.

PubMed [citation]

PMID:: 11941485

Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation.

Biffi A, Cesani M, Fumagalli F, Del Carro U, Baldoli C, Canale S, Gerevini S, Amadio S, Falautano M, Rovelli A, Comi G, Roncarolo MG, Sessa M.

Clin Genet. 2008 Oct;74(4):349-57. doi: 10.1111/j.1399-0004.2008.01058.x. Epub 2008 Sep 11.

PubMed [citation]

PMID:: 18786133

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004311949.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. This variant disrupts the p.Glu255 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11941485, 18786133). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with ARSA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 255 of the ARSA protein (p.Glu255Ala).

#	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

Last Updated: Sep 29, 2024

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