NM_000487.6(ARSA):c.937C>G (p.Arg313Gly) AND Metachromatic leukodystrophy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 13, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV001980760.8

Allele description [Variation Report for NM_000487.6(ARSA):c.937C>G (p.Arg313Gly)]

NM_000487.6(ARSA):c.937C>G (p.Arg313Gly)

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.937C>G (p.Arg313Gly)

HGVS:

NC_000022.11:g.50626196G>C
NG_009260.2:g.6984C>G
NM_000487.6:c.937C>GMANE SELECT
NM_001085425.3:c.937C>G
NM_001085426.3:c.937C>G
NM_001085427.3:c.937C>G
NM_001085428.3:c.679C>G
NM_001362782.2:c.679C>G
NP_000478.3:p.Arg313Gly
NP_001078894.2:p.Arg313Gly
NP_001078895.2:p.Arg313Gly
NP_001078896.2:p.Arg313Gly
NP_001078897.1:p.Arg227Gly
NP_001349711.1:p.Arg227Gly
NC_000022.10:g.51064624G>C

Protein change:

R227G

Links:

dbSNP: rs551472773

NCBI 1000 Genomes Browser:

rs551472773

Molecular consequence:

NM_000487.6:c.937C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.937C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.937C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.937C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.679C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.679C>G - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002269480	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 13, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21167507, 28667691, 28492532
SCV002764713	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Likely pathogenic (Nov 20, 2020)	maternal	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002269480

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 13, 2021)

germline

clinical testing

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

SCV002764713

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Likely pathogenic
(Nov 20, 2020)

maternal

clinical testing

Citation Link

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	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and structural analysis of metachromatic leukodystrophy patients in Indian population.

Shukla P, Vasisht S, Srivastava R, Gupta N, Ghosh M, Kumar M, Sharma R, Gupta AK, Kaur P, Kamate M, Gulati S, Kalra V, Phadke S, Singhi P, Dherai AJ, Kabra M.

J Neurol Sci. 2011 Feb 15;301(1-2):38-45. doi: 10.1016/j.jns.2010.11.007. Epub 2010 Dec 16.

PubMed [citation]

PMID:: 21167507

Subacute demyelinating peripheral neuropathy as a novel presentation of late infantile metachromatic leukodystrophy.

Gonorazky HD, Amburgey K, Yoon G, Vajsar J, Widjaja E, Dowling JJ.

Muscle Nerve. 2017 Nov;56(5):E41-E44. doi: 10.1002/mus.25737. Epub 2017 Jul 18. No abstract available.

PubMed [citation]

PMID:: 28667691

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002269480.3

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

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 313 of the ARSA protein (p.Arg313Gly). 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 variant has not been reported in the literature in individuals affected with ARSA-related conditions. 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 disrupts the p.Arg313 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21167507, 28667691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764713.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	maternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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