NM_000487.6(ARSA):c.1174C>G (p.Arg392Gly) AND Metachromatic leukodystrophy

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 29, 2022
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:: RCV003608418.2

Allele description

NM_000487.6(ARSA):c.1174C>G (p.Arg392Gly)

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.1174C>G (p.Arg392Gly)

HGVS:

NC_000022.11:g.50625615G>C
NG_009260.2:g.7565C>G
NM_000487.5:c.1174C>G
NM_000487.6:c.1174C>GMANE SELECT
NM_001085425.3:c.1174C>G
NM_001085426.3:c.1174C>G
NM_001085427.3:c.1174C>G
NM_001085428.3:c.916C>G
NM_001362782.2:c.916C>G
NP_000478.3:p.Arg392Gly
NP_001078894.2:p.Arg392Gly
NP_001078895.2:p.Arg392Gly
NP_001078896.2:p.Arg392Gly
NP_001078897.1:p.Arg306Gly
NP_001349711.1:p.Arg306Gly
NC_000022.10:g.51064043G>C

Protein change:

R306G

Molecular consequence:

NM_000487.6:c.1174C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.1174C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.1174C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.1174C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.916C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.916C>G - missense variant - [Sequence Ontology: SO:0001583]

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

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RecName: Full=Pecanex-like protein 4; AltName: Full=Hepatitis C virus F protein-...
RecName: Full=Pecanex-like protein 4; AltName: Full=Hepatitis C virus F protein-binding protein 2; Short=HCV F protein-binding protein 2; AltName: Full=Pecanex homolog protein 4
gi|206729932|sp|Q63HM2.4|PCX4_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004466121	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9452102, 20339381, 21167507, 26462614, 26553228, 28492532
SCV005046776	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004466121

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV005046776

Gelb Laboratory, University of Washington

no classification provided

not provided

not applicable

in vitro

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

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

Two novel mutations in the arylsulfatase A gene associated with juvenile (R390Q) and adult onset (H397Y) metachromatic leukodystrophy.

Coulter-Mackie MB, Gagnier L.

Hum Mutat. 1998;Suppl 1:S254-6. No abstract available.

PubMed [citation]

PMID:: 9452102

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

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV004466121.1

#	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 arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 392 of the ARSA protein (p.Arg392Gly). This variant is present in population databases (rs74315480, gnomAD 0.0009%). 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.Arg293 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452102, 20339381, 21167507, 26462614, 26553228). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant has not been reported in the literature in individuals affected with ARSA-related conditions.

#	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, SCV005046776.1

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

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: Jun 2, 2024

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