NM_000487.6(ARSA):c.1264del (p.Ser421_Leu422insTer) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 15, 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:: RCV000673517.6

Allele description [Variation Report for NM_000487.6(ARSA):c.1264del (p.Ser421_Leu422insTer)]

NM_000487.6(ARSA):c.1264del (p.Ser421_Leu422insTer)

Gene:

ARSA:arylsulfatase A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_000487.6(ARSA):c.1264del (p.Ser421_Leu422insTer)

HGVS:

NC_000022.11:g.50625411del
NG_009260.2:g.7769del
NM_000487.6:c.1264delMANE SELECT
NM_001085425.3:c.1264del
NM_001085426.3:c.1264del
NM_001085427.3:c.1264del
NM_001085428.3:c.1006del
NM_001362782.2:c.1006del
NP_000478.3:p.Ser421_Leu422insTer
NP_001078894.2:p.Ser421_Leu422insTer
NP_001078895.2:p.Ser421_Leu422insTer
NP_001078896.2:p.Ser421_Leu422insTer
NP_001078897.1:p.Ser335_Leu336insTer
NP_001349711.1:p.Ser335_Leu336insTer
NC_000022.10:g.51063839del
NM_000487.5:c.1264del
NM_000487.5:c.1264delC

Links:

dbSNP: rs755635209

NCBI 1000 Genomes Browser:

rs755635209

Molecular consequence:

NM_000487.6:c.1264del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085425.3:c.1264del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085426.3:c.1264del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085427.3:c.1264del - nonsense - [Sequence Ontology: SO:0001587]
NM_001085428.3:c.1006del - nonsense - [Sequence Ontology: SO:0001587]
NM_001362782.2:c.1006del - 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
SCV000798728	Counsyl	no assertion criteria provided	Likely pathogenic (Mar 22, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003817384	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004677688	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 15, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1670590, 9090526, 9096767, 11941485, 26462614, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798728

Counsyl

no assertion criteria provided

Likely pathogenic
(Mar 22, 2018)

unknown

clinical testing

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

SCV003817384

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 30, 2022)

germline

clinical testing

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

SCV004677688

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 15, 2023)

germline

clinical testing

PubMed (6)
[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

Complete mapping of a cystine knot and nested disulfides of recombinant human arylsulfatase A by multi-enzyme digestion and LC-MS analysis using CID and ETD.

Ni W, Lin M, Salinas P, Savickas P, Wu SL, Karger BL.

J Am Soc Mass Spectrom. 2013 Jan;24(1):125-33. doi: 10.1007/s13361-012-0510-z. Epub 2012 Dec 4.

PubMed [citation]

PMID:: 23208745
PMCID:: PMC3554868

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000798728.2

#	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 Revvity Omics, Revvity, SCV003817384.2

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004677688.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ARSA protein in which other variant(s) (p.Pro428Leu) have been determined to be pathogenic (PMID: 1670590, 9090526, 9096767, 11941485, 26462614). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 424522). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. This variant is present in population databases (rs755635209, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Leu422*) in the ARSA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) 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: Sep 29, 2024

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