NM_000487.6(ARSA):c.608A>G (p.Tyr203Cys) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 14, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000664907.5

Allele description [Variation Report for NM_000487.6(ARSA):c.608A>G (p.Tyr203Cys)]

NM_000487.6(ARSA):c.608A>G (p.Tyr203Cys)

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.608A>G (p.Tyr203Cys)

HGVS:

NC_000022.11:g.50626910T>C
NG_009260.2:g.6270A>G
NM_000487.6:c.608A>GMANE SELECT
NM_001085425.3:c.608A>G
NM_001085426.3:c.608A>G
NM_001085427.3:c.608A>G
NM_001085428.3:c.350A>G
NM_001362782.2:c.350A>G
NP_000478.3:p.Tyr203Cys
NP_001078894.2:p.Tyr203Cys
NP_001078895.2:p.Tyr203Cys
NP_001078896.2:p.Tyr203Cys
NP_001078897.1:p.Tyr117Cys
NP_001349711.1:p.Tyr117Cys
NC_000022.10:g.51065338T>C
NM_000487.5:c.608A>G

Protein change:

Y117C

Links:

UniProtKB/Swiss-Prot: VAR_007263; dbSNP: rs199476345

NCBI 1000 Genomes Browser:

rs199476345

Molecular consequence:

NM_000487.6:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.350A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.350A>G - 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
SCV000788937	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 4, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15720392, 10751093, 18786133 Citation Link,
SCV003444355	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 14, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23559313, 31694723, 7581401, 18786133, 28492532
SCV005046592	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (5) [See all records that cite these PMIDs] 16678723, 18786133, 26462614, 18693274, 37480112

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000788937

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Jan 4, 2017)

unknown

clinical testing

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

Citation Link,

SCV003444355

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 14, 2022)

germline

clinical testing

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

SCV005046592

Gelb Laboratory, University of Washington

no classification provided

not provided

not applicable

in vitro

PubMed (5)
[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
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Missense mutations as a cause of metachromatic leukodystrophy. Degradation of arylsulfatase A in the endoplasmic reticulum.

Poeppel P, Habetha M, Marcão A, Büssow H, Berna L, Gieselmann V.

FEBS J. 2005 Mar;272(5):1179-88.

PubMed [citation]

PMID:: 15720392

Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy.

Hermann S, Schestag F, Polten A, Kafert S, Penzien J, Zlotogora J, Baumann N, Gieselmann V.

Am J Med Genet. 2000 Mar 6;91(1):68-73.

PubMed [citation]

PMID:: 10751093

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000788937.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003444355.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr203 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23559313, 31694723). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ARSA function (PMID: 18786133). 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. ClinVar contains an entry for this variant (Variation ID: 68144). This variant is also known as Tyr201Cys or Y201C. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7581401, 18786133). This variant is present in population databases (rs199476345, gnomAD 0.007%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the ARSA protein (p.Tyr203Cys).

#	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, SCV005046592.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (5)

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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