NM_000487.6(ARSA):c.901C>T (p.Arg301Trp) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 18, 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:: RCV001353058.6

Allele description [Variation Report for NM_000487.6(ARSA):c.901C>T (p.Arg301Trp)]

NM_000487.6(ARSA):c.901C>T (p.Arg301Trp)

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.901C>T (p.Arg301Trp)

HGVS:

NC_000022.11:g.50626232G>A
NG_009260.2:g.6948C>T
NM_000487.6:c.901C>TMANE SELECT
NM_001085425.3:c.901C>T
NM_001085426.3:c.901C>T
NM_001085427.3:c.901C>T
NM_001085428.3:c.643C>T
NM_001362782.2:c.643C>T
NP_000478.3:p.Arg301Trp
NP_001078894.2:p.Arg301Trp
NP_001078895.2:p.Arg301Trp
NP_001078896.2:p.Arg301Trp
NP_001078897.1:p.Arg215Trp
NP_001349711.1:p.Arg215Trp
NC_000022.10:g.51064660G>A
NM_000487.5:c.901C>T

Protein change:

R215W

Links:

dbSNP: rs794727704

NCBI 1000 Genomes Browser:

rs794727704

Molecular consequence:

NM_000487.6:c.901C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.901C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.901C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.901C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

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

Observations:

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

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Mus musculus DnaJ heat shock protein family (Hsp40) member C25 (Dnajc25), mRNA
Mus musculus DnaJ heat shock protein family (Hsp40) member C25 (Dnajc25), mRNA
gi|239985467|ref|NM_001033165.3|

Nucleotide
major facilitator superfamily domain-containing protein 6 isoform a [Homo sapien...
major facilitator superfamily domain-containing protein 6 isoform a [Homo sapiens]
gi|144953907|ref|NP_060164.3|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001548182	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003444612	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 33335837, 12809637, 26462614, 30674982, 28492532
SCV005046515	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (4) [See all records that cite these PMIDs] 26462614, 30674982, 12809637, 37480112

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001548182

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 25, 2021)

germline

clinical testing

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

SCV003444612

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005046515

Gelb Laboratory, University of Washington

no classification provided

not provided

not applicable

in vitro

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	yes	1	not provided	not provided	1	not provided	clinical testing
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

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

Comprehensive clinical, biochemical, radiological and genetic analysis of 28 Turkish cases with suspected metachromatic leukodystrophy and their relatives.

Pekgül F, Eroğlu-Ertuğrul NG, Bekircan-Kurt CE, Erdem-Ozdamar S, Çetinkaya A, Tan E, Konuşkan B, Karaağaoğlu E, Topçu M, Akarsu NA, Oguz KK, Anlar B, Özkara HA.

Mol Genet Metab Rep. 2020 Dec;25:100688. doi: 10.1016/j.ymgmr.2020.100688.

PubMed [citation]

PMID:: 33335837
PMCID:: PMC7734308

See all PubMed Citations (7)

Details of each submission

From Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SCV001548182.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	discovery		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003444612.2

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

Description

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 expected to disrupt ARSA protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg301 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 30674982, 33335837), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 1048519). This variant is also known as R299W. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809637, 26462614, 30674982). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 301 of the ARSA protein (p.Arg301Trp).

#	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, SCV005046515.1

#	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: Sep 29, 2024

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