NM_000487.6(ARSA):c.926A>T (p.Glu309Val) AND Metachromatic leukodystrophy

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 6, 2022
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:: RCV002527037.2

Allele description

NM_000487.6(ARSA):c.926A>T (p.Glu309Val)

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.926A>T (p.Glu309Val)

HGVS:

NC_000022.11:g.50626207T>A
NG_009260.2:g.6973A>T
NM_000487.6:c.926A>TMANE SELECT
NM_001085425.3:c.926A>T
NM_001085426.3:c.926A>T
NM_001085427.3:c.926A>T
NM_001085428.3:c.668A>T
NM_001362782.2:c.668A>T
NP_000478.3:p.Glu309Val
NP_001078894.2:p.Glu309Val
NP_001078895.2:p.Glu309Val
NP_001078896.2:p.Glu309Val
NP_001078897.1:p.Glu223Val
NP_001349711.1:p.Glu223Val
NC_000022.10:g.51064635T>A
NM_000487.5:c.926A>T

Protein change:

E223V

Links:

dbSNP: rs1085308016

NCBI 1000 Genomes Browser:

rs1085308016

Molecular consequence:

NM_000487.6:c.926A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.926A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.926A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.926A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.668A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.668A>T - 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
SCV003027871	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 6, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18768108, 19606494, 26462614, 30057904, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003027871

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 6, 2022)

germline

clinical testing

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

Citations

PubMed

Identification of two novel arylsulfatase A mutations with a polymorphism as a cause of metachromatic leukodystrophy.

Onder E, Sinici I, Müjgan Sönmez F, Topçu M, Ozkara HA.

Neurol Res. 2009 Feb;31(1):60-6. doi: 10.1179/016164108X323762. Epub 2008 Sep 3.

PubMed [citation]

PMID:: 18768108

Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy.

Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Naldini L, Comi G, Sessa M, Biffi A.

Hum Mutat. 2009 Oct;30(10):E936-45. doi: 10.1002/humu.21093.

PubMed [citation]

PMID:: 19606494

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV003027871.2

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

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 309 of the ARSA protein (p.Glu309Val). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. 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.Glu309 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18768108, 19606494, 26462614, 30057904). 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: 427192).

#	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: Mar 5, 2024

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