NM_000487.6(ARSA):c.1150G>A (p.Glu384Lys) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 27, 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:: RCV000078936.24

Allele description [Variation Report for NM_000487.6(ARSA):c.1150G>A (p.Glu384Lys)]

NM_000487.6(ARSA):c.1150G>A (p.Glu384Lys)

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.1150G>A (p.Glu384Lys)

Other names:

E382K

HGVS:

NC_000022.11:g.50625639C>T
NG_009260.2:g.7541G>A
NM_000487.6:c.1150G>AMANE SELECT
NM_001085425.3:c.1150G>A
NM_001085426.3:c.1150G>A
NM_001085427.3:c.1150G>A
NM_001085428.3:c.892G>A
NM_001362782.2:c.892G>A
NP_000478.3:p.Glu384Lys
NP_000478.3:p.Glu384Lys
NP_001078894.2:p.Glu384Lys
NP_001078895.2:p.Glu384Lys
NP_001078896.2:p.Glu384Lys
NP_001078897.1:p.Glu298Lys
NP_001349711.1:p.Glu298Lys
NC_000022.10:g.51064067C>T
NM_000487.5:c.1150G>A

Protein change:

E298K; GLU382LYS

Links:

OMIM: 607574.0036; dbSNP: rs74315479

NCBI 1000 Genomes Browser:

rs74315479

Molecular consequence:

NM_000487.6:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.1150G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.892G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functionally_normal [Sequence Ontology: SO:0002219] - 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
SCV000752522	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7906588, 19021637, 20339381, 26462614, 15375602, 28492532
SCV000793445	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Aug 18, 2017)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24001781, 7906588, 7866401, 27261095, 26462614, 19021637, 15375602 Citation Link,
SCV001141461	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002081642	Natera, Inc.	no assertion criteria provided	Pathogenic (May 6, 2021)	germline	clinical testing
SCV005046783	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (4) [See all records that cite these PMIDs] 26462614, 9452102, 31922725, 37480112

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
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

Molecular bases of metachromatic leukodystrophy in Polish patients.

Lugowska A, Płoski R, Włodarski P, Tylki-Szymańska A.

J Hum Genet. 2010 Jun;55(6):394-6. doi: 10.1038/jhg.2010.25. Epub 2010 Mar 26.

PubMed [citation]

PMID:: 20339381

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

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752522.7

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 384 of the ARSA protein (p.Glu384Lys). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs74315479, gnomAD 0.007%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7906588, 15375602, 19021637, 20339381, 26462614). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1144G>A or E382K. ClinVar contains an entry for this variant (Variation ID: 3084). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ARSA protein function with a negative predictive value of 95%. Studies have shown that this missense change results in exon 7 skipping and introduces a new termination codon (PMID: 15375602). However the mRNA is not expected to undergo nonsense-mediated decay. 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 Counsyl, SCV000793445.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Mendelics, SCV001141461.1

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

From Natera, Inc., SCV002081642.1

#	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

From Gelb Laboratory, University of Washington, SCV005046783.1

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

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: Nov 30, 2024

ClinVar

Relating variation to medicine