NM_000487.6(ARSA):c.433C>T (p.Arg145Ter) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV001042235.7

Allele description [Variation Report for NM_000487.6(ARSA):c.433C>T (p.Arg145Ter)]

NM_000487.6(ARSA):c.433C>T (p.Arg145Ter)

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.433C>T (p.Arg145Ter)

Other names:

p.Arg145Ter

HGVS:

NC_000022.11:g.50627198G>A
NG_009260.2:g.5982C>T
NM_000487.6:c.433C>TMANE SELECT
NM_001085425.3:c.433C>T
NM_001085426.3:c.433C>T
NM_001085427.3:c.433C>T
NM_001085428.3:c.175C>T
NM_001362782.2:c.175C>T
NP_000478.3:p.Arg145Ter
NP_001078894.2:p.Arg145Ter
NP_001078895.2:p.Arg145Ter
NP_001078896.2:p.Arg145Ter
NP_001078897.1:p.Arg59Ter
NP_001349711.1:p.Arg59Ter
NC_000022.10:g.51065626G>A
NM_000487.5:c.433C>T

Protein change:

R145*

Links:

dbSNP: rs199476373

NCBI 1000 Genomes Browser:

rs199476373

Molecular consequence:

NM_000487.6:c.433C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085425.3:c.433C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085426.3:c.433C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085427.3:c.433C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001085428.3:c.175C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001362782.2:c.175C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

Unknown function

Observations:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001205907	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8962139, 10477432, 28492532
SCV002754482	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001205907

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

germline

clinical testing

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

SCV002754482

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy.

Hess B, Saftig P, Hartmann D, Coenen R, Lüllmann-Rauch R, Goebel HH, Evers M, von Figura K, D'Hooge R, Nagels G, De Deyn P, Peters C, Gieselmann V.

Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14821-6.

PubMed [citation]

PMID:: 8962139
PMCID:: PMC26220

Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients.

Gort L, Coll MJ, Chabás A.

Hum Mutat. 1999;14(3):240-8.

PubMed [citation]

PMID:: 10477432

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001205907.5

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

Description

This sequence change creates a premature translational stop signal (p.Arg145*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. ClinVar contains an entry for this variant (Variation ID: 840281). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV002754482.1

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

Description

A Heterozygous nonsense variation in exon 3 of the ARSA gene that results in stop codon and premature truncation of the protein at codon 145. The observed variant c.433C>T(p.Arg145Ter)) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

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

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine