NM_000487.6(ARSA):c.1269del (p.Ala424fs) AND Metachromatic leukodystrophy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 24, 2019
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:: RCV001212980.6

Allele description [Variation Report for NM_000487.6(ARSA):c.1269del (p.Ala424fs)]

NM_000487.6(ARSA):c.1269del (p.Ala424fs)

Gene:

ARSA:arylsulfatase A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_000487.6(ARSA):c.1269del (p.Ala424fs)

HGVS:

NC_000022.11:g.50625406del
NG_009260.2:g.7774del
NM_000487.6:c.1269delMANE SELECT
NM_001085425.3:c.1269del
NM_001085426.3:c.1269del
NM_001085427.3:c.1269del
NM_001085428.3:c.1011del
NM_001362782.2:c.1011del
NP_000478.3:p.Ala424fs
NP_001078894.2:p.Ala424fs
NP_001078895.2:p.Ala424fs
NP_001078896.2:p.Ala424fs
NP_001078897.1:p.Ala338fs
NP_001349711.1:p.Ala338fs
NC_000022.10:g.51063834del
NM_000487.5:c.1269del

Protein change:

A338fs

Links:

dbSNP: rs2082646919

NCBI 1000 Genomes Browser:

rs2082646919

Molecular consequence:

NM_000487.6:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085425.3:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085426.3:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085427.3:c.1269del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001085428.3:c.1011del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001362782.2:c.1011del - 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
SCV001384593	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 24, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11941485, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001384593

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 24, 2019)

germline

clinical testing

PubMed (2)
[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

Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.

Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M.

Hum Genet. 2002 Apr;110(4):351-5. Epub 2002 Mar 8.

PubMed [citation]

PMID:: 11941485

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001384593.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.Pro428 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11941485,¬†26462614,¬†9096767,¬†9090526). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals with ARSA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ARSA gene (p.Ala424Leufs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acids of the ARSA protein.

#	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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