NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 6, 2023
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:: RCV000078942.12

Allele description [Variation Report for NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer)]

NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer)

Gene:

ARSA:arylsulfatase A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_000487.6(ARSA):c.195del (p.Phe64_Tyr65insTer)

HGVS:

NC_000022.11:g.50627585del
NG_009260.2:g.5595del
NM_000487.6:c.195delMANE SELECT
NM_001085425.3:c.195del
NM_001085426.3:c.195del
NM_001085427.3:c.195del
NM_001085428.3:c.-34-179del
NM_001362782.2:c.-34-179del
NP_000478.3:p.Phe64_Tyr65insTer
NP_001078894.2:p.Phe64_Tyr65insTer
NP_001078895.2:p.Phe64_Tyr65insTer
NP_001078896.2:p.Phe64_Tyr65insTer
NC_000022.10:g.51066013del
NM_000487.5:c.195del
NM_000487.5:c.195delC

Links:

dbSNP: rs398123414

NCBI 1000 Genomes Browser:

rs398123414

Molecular consequence:

NM_001085428.3:c.-34-179del - intron variant - [Sequence Ontology: SO:0001627]
NM_001362782.2:c.-34-179del - intron variant - [Sequence Ontology: SO:0001627]
NM_000487.6:c.195del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085425.3:c.195del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085426.3:c.195del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085427.3:c.195del - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000586685	Neurometabolisches Labor, University hospital Tuebingen	criteria provided, single submitter (BÃ¶hringer et al. (Hum Mutat. 2017))	Pathogenic (May 1, 2017)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000788912	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Dec 23, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001203142	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8962139, 10477432, 24001781, 28762252, 28492532
SCV002083908	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 20, 2020)	germline	clinical testing

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	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 (5)

Details of each submission

From Neurometabolisches Labor, University hospital Tuebingen, SCV000586685.1

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

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

From Counsyl, SCV000788912.1

#	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 Invitae, SCV001203142.5

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

Description

This sequence change creates a premature translational stop signal (p.Tyr65*) 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 present in population databases (rs398123414, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with metachromatic leukodystrophy (PMID: 24001781, 28762252). This variant is also known as 189delC, Y63X. ClinVar contains an entry for this variant (Variation ID: 93121). 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 Natera, Inc., SCV002083908.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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