NM_000487.6(ARSA):c.607T>C (p.Tyr203His) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 13, 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:: RCV001290420.7

Allele description [Variation Report for NM_000487.6(ARSA):c.607T>C (p.Tyr203His)]

NM_000487.6(ARSA):c.607T>C (p.Tyr203His)

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.607T>C (p.Tyr203His)

HGVS:

NC_000022.11:g.50626911A>G
NG_009260.2:g.6269T>C
NM_000487.6:c.607T>CMANE SELECT
NM_001085425.3:c.607T>C
NM_001085426.3:c.607T>C
NM_001085427.3:c.607T>C
NM_001085428.3:c.349T>C
NM_001362782.2:c.349T>C
NP_000478.3:p.Tyr203His
NP_001078894.2:p.Tyr203His
NP_001078895.2:p.Tyr203His
NP_001078896.2:p.Tyr203His
NP_001078897.1:p.Tyr117His
NP_001349711.1:p.Tyr117His
NC_000022.10:g.51065339A>G
NM_000487.5:c.607T>C

Protein change:

Y117H

Links:

dbSNP: rs2082680103

NCBI 1000 Genomes Browser:

rs2082680103

Molecular consequence:

NM_000487.6:c.607T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.607T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.607T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.607T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.349T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.349T>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
SCV001478467	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	no assertion criteria provided	Pathogenic	inherited	clinical testing
SCV002125651	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23559313, 31694723, 18786133, 28492532
SCV002798452	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 13, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005046593	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (3) [See all records that cite these PMIDs] 23559313, 31694723, 37480112

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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	inherited	yes	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

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

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

See all PubMed Citations (6)

Details of each submission

From Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,, SCV001478467.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002125651.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 203 of the ARSA protein (p.Tyr203His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 23559313, 31694723). 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: 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. ClinVar contains an entry for this variant (Variation ID: 996131). This variant is also known as c.601 T>C (p.Tyr201His).

#	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 Fulgent Genetics, Fulgent Genetics, SCV002798452.1

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

#	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 Gelb Laboratory, University of Washington, SCV005046593.1

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

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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