VCV000003050.37 - ClinVar

NM_000487.6(ARSA):c.1055A>G (p.Asn352Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(19)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign; other

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000487.6(ARSA):c.1055A>G (p.Asn352Ser)

Variation ID: 3050 Accession: VCV000003050.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50625988 (GRCh38) [ NCBI UCSC ] 22: 51064416 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 2, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.1055A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000478.3:p.Asn352Ser	missense
NM_001085425.3:c.1055A>G	NP_001078894.2:p.Asn352Ser	missense
NM_001085426.3:c.1055A>G	NP_001078895.2:p.Asn352Ser	missense
NM_001085427.3:c.1055A>G	NP_001078896.2:p.Asn352Ser	missense
NM_001085428.3:c.797A>G	NP_001078897.1:p.Asn266Ser	missense
NM_001362782.2:c.797A>G	NP_001349711.1:p.Asn266Ser	missense
NC_000022.11:g.50625988T>C
NC_000022.10:g.51064416T>C
NG_009260.2:g.7192A>G

... more HGVS ... less HGVS

Protein change

N352S, N266S

Other names

N350S

Canonical SPDI

NC_000022.11:50625987:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

functionally_normal; Sequence Ontology [ SO:0002219]

As described in PMID: 37480112, ARSA enzymatic activity >13% of wild type is taken as benign and likely does not contribute to disease. [submitted by Gelb Laboratory, University of Washington]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.22484 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.16546

The Genome Aggregation Database (gnomAD) 0.19530

Trans-Omics for Precision Medicine (TOPMed) 0.21494

Exome Aggregation Consortium (ExAC) 0.21660

1000 Genomes Project 0.22484

1000 Genomes Project 30x 0.22892

Links

dbSNP: rs2071421 ClinGen: CA115954 OMIM: 607574.0002 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 2574462 to determine the location of this allele on current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ARSA		-	-	GRCh38 GRCh37	1256	1424

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
ARYLSULFATASE A POLYMORPHISM	Benign (1)	no assertion criteria provided	Dec 1, 1997	RCV000003191.11
Metachromatic leukodystrophy	Benign/Likely benign (8)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000020310.31
not provided	Benign/Likely benign; other (4)	criteria provided, multiple submitters, no conflicts	Nov 11, 2021	RCV000078931.25
not specified	Benign (5)	criteria provided, single submitter	-	RCV000249834.19
Metachromatic leukodystrophy, juvenile type	Uncertain significance (1)	no assertion criteria provided	-	RCV001357207.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304453.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Oct 11, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511542.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
other (Jul 24, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110791.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 2574462 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA Number of individuals with the variant: 581 Sex: mixed
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141462.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737289.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001733012.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005207843.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	SIB Swiss Institute of Bioinformatics Accession: SCV000883252.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Publications: PubMed (2) PubMed: 11941485‚ 2574462 Comment: This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is … (more) This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462). (less)
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000439433.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Nov 11, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001871299.3 First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 2574462, 21648305, 8897113, 30026549, 32437521, 26577183, 31670782, 32470555, 31312839, 31694723, 23581857)
Benign (Dec 01, 1997)	no assertion criteria provided Method: literature only	ARYLSULFATASE A POLYMORPHISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023349.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018	Publications: PubMed (2) PubMed: 7866401‚ 9402957 Comment on evidence: In a homozygote for ARSA deficiency (250100), Gieselmann et al. (1989) demonstrated that an A-to-G transition in the polyadenylation signal downstream of the stop codon, … (more) In a homozygote for ARSA deficiency (250100), Gieselmann et al. (1989) demonstrated that an A-to-G transition in the polyadenylation signal downstream of the stop codon, from AATAAC to AGTAAC, was responsible for the severe deficiency of a 2.1-kb RNA species and the diminished synthesis of ARSA (607574.0001). A second mutation, asn350-to-serine, resulting from an A-to-G transition, appeared to be responsible for the small size of ARSA produced by pseudodeficiency fibroblasts because it led to loss of an N-glycosylation site. It was not, however, responsible for the defective synthesis of enzyme. The asn350-to-ser mutation is a polymorphism that does not affect the activity or stability of the enzyme, whereas the other mutation causes the loss of about 90% of ARSA mRNA, which explains the loss of 90% of ARSA crossreacting material and enzyme activity. The 'pseudodeficiency' allele, found in a frequency of approximately 10% in many populations, is associated with 2 A-to-G transitions in cis in the ARSA gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, Ott et al. (1997) studied 400 individuals in the African, European, Indian, and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varies from 0.01 in Indians and 0.06 in Europeans to 0.21 in East Asians and 0.32 in Africans. The frequencies of both mutations occurring together range from almost nonexistent in the Africans and East Asians, to 0.075 in Europeans and 0.125 in Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and 8 multigeneration families with 6 polymorphism-identifying restriction enzymes showed that, of the 5 haplotypes found in the general population, only 1 was linked to the double mutations. Alleles among the 4 populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans, whose alleles were discordant. These results were considered consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa approximately 100,000 to 200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages. (less)
Benign (Dec 10, 2019)	no assertion criteria provided Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456232.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740695.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954847.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Metachromatic leukodystrophy, juvenile type Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552597.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: ClinVar reports this variant as a Pseudodeficiency allele from ClinVar. Homozygosity for the p.Asn350Ser variant alone results in 50% or more of the mean control … (more) ClinVar reports this variant as a Pseudodeficiency allele from ClinVar. Homozygosity for the p.Asn350Ser variant alone results in 50% or more of the mean control ARSA enzyme activity in leukocytes.Â¬â€ Allele frequency is common in at least one population database (frequency: 39.478% in ExAC) based on the frequency threshold of 1.151% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462). (ClinVar: SIB Swiss Institute of Bioinformatics) (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925236.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931644.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: in vitro	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: not applicable Allele origin: not applicable	Gelb Laboratory, University of Washington Accession: SCV005046796.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Publications: PubMed (3) PubMed: 31694723‚ 30652456‚ 37480112 Comment on evidence: 0 to < 2% of wild type ARSA enzymatic activity is taken as severe, 2 to <4% is taken moderate, 4 to 13% is taken … (more) 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 (less) Method: tandem mass spectrometry used to measure enymatic activity Result: 65.37% of wild type enzymatic activity
not provided (-)	no classification provided Method: literature only	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040685.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1130 BookShelf: NBK1130
click to load more click to collapse

Comment:

This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

ClinVar reports this variant as a Pseudodeficiency allele from ClinVar. Homozygosity for the p.Asn350Ser variant alone results in 50% or more of the mean control ARSA enzyme activity in leukocytes.Â¬â€ Allele frequency is common in at least one population database (frequency: 39.478% in ExAC) based on the frequency threshold of 1.151% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.This variant is interpreted as Benign - Stand Alone, for Metachromatic leukodystrophy, autosomal recessive. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (https://www.ncbi.nlm.nih.gov/pubmed/11941485) (https://www.ncbi.nlm.nih.gov/pubmed/2574462). (ClinVar: SIB Swiss Institute of Bioinformatics)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
functionally_normal (SO:0002219)	tandem mass spectrometry used to measure enymatic activity Method citation(s): PubMed(1)	65.37% of wild type enzymatic activity	Gelb Laboratory, University of Washington Accession: SCV005046796.1	Publications PubMed (3) Comment: As described in PMID: 37480112, ARSA enzymatic activity >13% of wild type is taken as benign and likely does not contribute to disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Arylsulfatase A Deficiency.	Adam MP	-	2024	PMID: 20301309
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.	Trinidad M	Genome biology	2023	PMID: 37480112
Three novel variants in the arylsulfatase A (ARSA) gene in patients with metachromatic leukodystrophy (MLD).	Hettiarachchi D	BMC research notes	2019	PMID: 31694723
[Late infantile metachromatic leukodystrophy: case report].	Alvarez-Pabón Y	Archivos argentinos de pediatria	2019	PMID: 30652456
Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.	Regis S	Human genetics	2002	PMID: 11941485
Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency.	Ott R	Human genetics	1997	PMID: 9402957
Molecular genetics of metachromatic leukodystrophy.	Gieselmann V	Human mutation	1994	PMID: 7866401
Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site.	Gieselmann V	Proceedings of the National Academy of Sciences of the United States of America	1989	PMID: 2574462
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ARSA	-	-	-	-

Text-mined citations for rs2071421 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000487.6(ARSA):c.1055A>G (p.Asn352Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2071421 ...