NM_000487.6(ARSA):c.899T>C (p.Leu300Ser) AND Metachromatic leukodystrophy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 9, 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:: RCV001854230.12

Allele description [Variation Report for NM_000487.6(ARSA):c.899T>C (p.Leu300Ser)]

NM_000487.6(ARSA):c.899T>C (p.Leu300Ser)

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.899T>C (p.Leu300Ser)

HGVS:

NC_000022.11:g.50626234A>G
NG_009260.2:g.6946T>C
NM_000487.6:c.899T>CMANE SELECT
NM_001085425.3:c.899T>C
NM_001085426.3:c.899T>C
NM_001085427.3:c.899T>C
NM_001085428.3:c.641T>C
NM_001362782.2:c.641T>C
NP_000478.3:p.Leu300Ser
NP_001078894.2:p.Leu300Ser
NP_001078895.2:p.Leu300Ser
NP_001078896.2:p.Leu300Ser
NP_001078897.1:p.Leu214Ser
NP_001349711.1:p.Leu214Ser
NC_000022.10:g.51064662A>G
NM_000487.4:c.893T>C
NM_000487.5:c.899T>C
p.L298S

Protein change:

L214S

Links:

UniProtKB/Swiss-Prot: VAR_054196; dbSNP: rs199476389

NCBI 1000 Genomes Browser:

rs199476389

Molecular consequence:

NM_000487.6:c.899T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.899T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.899T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.899T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.641T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.641T>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
SCV002295974	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9819708, 31312839, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002295974

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 9, 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

Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy: identification of two novel mutations.

Kurosawa K, Ida H, Eto Y.

J Inherit Metab Dis. 1998 Oct;21(7):781-2. No abstract available.

PubMed [citation]

PMID:: 9819708

Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone.

Lee JS, Kanai K, Suzuki M, Kim WS, Yoo HS, Fu Y, Kim DK, Jung BC, Choi M, Oh KW, Li Y, Nakatani M, Nakazato T, Sekimoto S, Funayama M, Yoshino H, Kubo SI, Nishioka K, Sakai R, Ueyama M, Mochizuki H, Lee HJ, et al.

Brain. 2019 Sep 1;142(9):2845-2859. doi: 10.1093/brain/awz205.

PubMed [citation]

PMID:: 31312839

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002295974.3

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

Description

Experimental studies have shown that this missense change affects ARSA function (PMID: 9819708, 31312839). 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: 68157). This variant is also known as L298S. This missense change has been observed in individuals with metachromatic leukodystrophy (PMID: 9819708, 31312839). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 300 of the ARSA protein (p.Leu300Ser). 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.

#	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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