NM_000487.6(ARSA):c.855-1G>A AND Metachromatic leukodystrophy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 26, 2022
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:: RCV001042683.10

Allele description [Variation Report for NM_000487.6(ARSA):c.855-1G>A]

NM_000487.6(ARSA):c.855-1G>A

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.855-1G>A

HGVS:

NC_000022.11:g.50626279C>T
NG_009260.2:g.6901G>A
NG_146552.1:g.50C>T
NM_000487.6:c.855-1G>AMANE SELECT
NM_001085425.3:c.855-1G>A
NM_001085426.3:c.855-1G>A
NM_001085427.3:c.855-1G>A
NM_001085428.3:c.597-1G>A
NM_001362782.2:c.597-1G>A
NC_000022.10:g.51064707C>T
NM_000487.5:c.855-1G>A

Links:

dbSNP: rs754898479

NCBI 1000 Genomes Browser:

rs754898479

Molecular consequence:

NM_000487.6:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001085425.3:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001085426.3:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001085427.3:c.855-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001085428.3:c.597-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001362782.2:c.597-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054] - Comment(s)

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
SCV001206382	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 24, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14571263, 18786133, 28492532
SCV002598634	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18786133, 33855715, 14571263 Citation Link,
SCV005046710	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (5) [See all records that cite these PMIDs] 18786133, 26462614, 23559313, 27289174, 37480112

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001206382

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 24, 2020)

germline

clinical testing

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

SCV002598634

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 26, 2022)

germline

clinical testing

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

Citation Link,

SCV005046710

Gelb Laboratory, University of Washington

no classification provided

not provided

not applicable

in vitro

PubMed (5)
[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	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients.

Fumagalli F, Zambon AA, Rancoita PMV, Baldoli C, Canale S, Spiga I, Medaglini S, Penati R, Facchini M, Ciotti F, Sarzana M, Lorioli L, Cesani M, Natali Sora MG, Del Carro U, Cugnata F, Antonioli G, Recupero S, Calbi V, Di Serio C, Aiuti A, Biffi A, et al.

J Inherit Metab Dis. 2021 Sep;44(5):1151-1164. doi: 10.1002/jimd.12388. Epub 2021 May 4.

PubMed [citation]

PMID:: 33855715

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001206382.5

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID:14571263). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14571263, 18786133). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.849-1G>A in the literature. This variant is present in population databases (rs754898479, ExAC 0.002%). This sequence change affects an acceptor splice site in intron 4 of the ARSA gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002598634.1

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

Description

Variant summary: ARSA c.855-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Regis_2004). The variant allele was found at a frequency of 8.1e-06 in 246424 control chromosomes. c.855-1G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Regis_2004, Fumagalli_2021). These data indicate that the variant is associated with disease. One publication reports experimental evidence evaluating an impact on protein function, with the variant resulting in reduced enzyme activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Gelb Laboratory, University of Washington, SCV005046710.1

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

Description

"0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken as mild, and >13% is taken as benign, see PMID: 37480112"

PubMed [ID: 37480112]

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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine