NM_000487.6(ARSA):c.1489_1492dup (p.Arg498fs) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 17, 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:: RCV000169193.6

Allele description [Variation Report for NM_000487.6(ARSA):c.1489_1492dup (p.Arg498fs)]

NM_000487.6(ARSA):c.1489_1492dup (p.Arg498fs)

Gene:

ARSA:arylsulfatase A [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_000487.6(ARSA):c.1489_1492dup (p.Arg498fs)

HGVS:

NC_000022.11:g.50625185_50625188dup
NG_009260.2:g.7994_7997dup
NM_000487.6:c.1489_1492dupMANE SELECT
NM_001085425.3:c.1489_1492dup
NM_001085426.3:c.1489_1492dup
NM_001085427.3:c.1489_1492dup
NM_001085428.3:c.1231_1234dup
NM_001362782.2:c.1231_1234dup
NP_000478.3:p.Arg498fs
NP_001078894.2:p.Arg498fs
NP_001078895.2:p.Arg498fs
NP_001078896.2:p.Arg498fs
NP_001078897.1:p.Arg412fs
NP_001349711.1:p.Arg412fs
NC_000022.10:g.51063610_51063611insGGGG
NC_000022.10:g.51063613_51063616dup
NM_000487.5:c.1489_1492dup
NM_000487.5:c.1489_1492dupCCCC

Protein change:

R412fs

Links:

dbSNP: rs774153480

NCBI 1000 Genomes Browser:

rs774153480

Molecular consequence:

NM_000487.6:c.1489_1492dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085425.3:c.1489_1492dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085426.3:c.1489_1492dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085427.3:c.1489_1492dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085428.3:c.1231_1234dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001362782.2:c.1231_1234dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002060162	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 10, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003444495	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19021637, 26462614, 12809638, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002060162

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Likely pathogenic
(Nov 10, 2021)

unknown

clinical testing

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

Citation Link,

SCV003444495

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 17, 2023)

germline

clinical testing

PubMed (4)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD).

Eng B, Nakamura LN, O'Reilly N, Schokman N, Nowaczyk MM, Krivit W, Waye JS.

Hum Mutat. 2003 Nov;22(5):418-9.

PubMed [citation]

PMID:: 14517960

Molecular and clinical consequences of novel mutations in the arylsulfatase A gene.

Ługowska A, Wlodarski P, Płoski R, Mierzewska H, Dudzińska M, Matheisel A, Swietochowska H, Tylki-Szymańska A.

Clin Genet. 2009 Jan;75(1):57-64. doi: 10.1111/j.1399-0004.2008.01108.x. Epub 2008 Nov 17.

PubMed [citation]

PMID:: 19021637

See all PubMed Citations (5)

Details of each submission

From Myriad Genetics, Inc., SCV002060162.2

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

Description

NM_000487.5(ARSA):c.1489_1492dupCCCC(R498Pfs*76) is a read through frameshift variant classified as likely pathogenic in the context of metachromatic leukodystrophy. R498Pfs*76 has been observed in cases with relevant disease (PMID: 14517960). Functional assessments of this variant are not available in the literature. R498Pfs*76 has been observed in population frequency databases (gnomAD: NFE 0.016%). In summary, NM_000487.5(ARSA):c.1489_1492dupCCCC(R498Pfs*76) is a read through frameshift variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening.

#	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, SCV003444495.2

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the ARSA protein. Other variant(s) that result in a similarly extended protein product (p.Arg498Profs*75) have been determined to be pathogenic (PMID: 19021637, 26462614). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 188843). This variant is also known as 2590_2591insCCCC. This frameshift has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809638). This variant is present in population databases (rs774153480, gnomAD 0.005%). This sequence change results in a frameshift in the ARSA gene (p.Arg498Profs*76). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the ARSA protein and extend the protein by 63 additional amino acid residues.

#	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 28, 2024

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