NM_000487.6(ARSA):c.883G>A (p.Gly295Ser) AND Metachromatic leukodystrophy

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Dec 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:: RCV000150060.30

Allele description [Variation Report for NM_000487.6(ARSA):c.883G>A (p.Gly295Ser)]

NM_000487.6(ARSA):c.883G>A (p.Gly295Ser)

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.883G>A (p.Gly295Ser)

HGVS:

NC_000022.11:g.50626250C>T
NG_009260.2:g.6930G>A
NM_000487.6:c.883G>AMANE SELECT
NM_001085425.3:c.883G>A
NM_001085426.3:c.883G>A
NM_001085427.3:c.883G>A
NM_001085428.3:c.625G>A
NM_001362782.2:c.625G>A
NP_000478.3:p.Gly295Ser
NP_000478.3:p.Gly295Ser
NP_001078894.2:p.Gly295Ser
NP_001078895.2:p.Gly295Ser
NP_001078896.2:p.Gly295Ser
NP_001078897.1:p.Gly209Ser
NP_001349711.1:p.Gly209Ser
NC_000022.10:g.51064678C>T
NM_000487.4:c.877G>A
NM_000487.5:c.883G>A
p.G293S

Protein change:

G209S

Links:

UniProtKB/Swiss-Prot: VAR_054194; dbSNP: rs199476349

NCBI 1000 Genomes Browser:

rs199476349

Molecular consequence:

NM_000487.6:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085425.3:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085426.3:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085427.3:c.883G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001085428.3:c.625G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362782.2:c.625G>A - 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

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
SCV000439436	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15326627, 18786133 Citation Link,
SCV000486786	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 9, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18786133, 15326627 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001588981	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15326627, 18786133, 28492532
SCV001994819	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 28, 2021)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002081653	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 19, 2021)	germline	clinical testing
SCV004241246	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18786133, 36240581, 15326627 Citation Link,
SCV005046522	Gelb Laboratory, University of Washington	no classification provided	not provided	not applicable	in vitro	PubMed (4) [See all records that cite these PMIDs] 15326627, 18786133, 30674982, 37480112

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	paternal	yes	not provided	not provided	not provided	not provided	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

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

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000439436.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The ARSA c.883G>A (p.Gly295Ser) variant (previously reported as c.887G>A, p.Gly293Ser) has been reported in two studies in which it was found in a compound heterozygous state with a second missense variant in a total of three individuals with metachromatic leukodystrophy (Berna et al. 2004; Biffi et al. 2008). One of the compound heterozygous individuals was also heterozygous for two additional variants (one known phenotype modifier and one functional polymorphism known to reduce enzyme activity) but did not carry the most common pseudodeficiency alleles (Biffi et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. However, this frequency is based on two alleles only in a region of good sequence coverage, suggesting the variant is rare. The p.Gly295Ser variant is located in a conserved residue in a functionally important domain of the protein. Functional studies in BHK-21 cells demonstrated the variant to be a null allele, causing the complete loss of enzyme activity (Berna et al. 2004). Based on the evidence, the p.Gly295Ser variant is classified as likely pathogenic for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV000486786.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001588981.4

#	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 missense change affects ARSA function (PMID: 15326627). 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. ClinVar contains an entry for this variant (Variation ID: 68154). This variant is also known as Gly293Ser. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 15326627, 18786133). This variant is present in population databases (rs199476349, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 295 of the ARSA protein (p.Gly295Ser).

#	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 Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001994819.1

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

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

From Natera, Inc., SCV002081653.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241246.1

#	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.883G>A (p.Gly295Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248784 control chromosomes. c.883G>A has been reported in the literature in multiple compound heterozygous individuals affected with Metachromatic Leukodystrophy, including with adult and early juvenille onset (e.g. Berna_2004, Biffi_2008, Santhanakumaran_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in null enzyme activity in vitro (e.g. Berna_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15326627, 18786133, 36240581). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4) or likely pathogenic (n=2). 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, SCV005046522.1

#	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: Oct 8, 2024

Relating variation to medicine