VCV000003060.44 - ClinVar

NM_000487.6(ARSA):c.931G>A (p.Gly311Ser)

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.

(14)

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.

Pathogenic/Likely pathogenic

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.931G>A (p.Gly311Ser)

Variation ID: 3060 Accession: VCV000003060.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.33 22: 50626202 (GRCh38) [ NCBI UCSC ] 22: 51064630 (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	Apr 4, 2013	Oct 20, 2024	Sep 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000487.6:c.931G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000478.3:p.Gly311Ser	missense
NM_001085425.3:c.931G>A	NP_001078894.2:p.Gly311Ser	missense
NM_001085426.3:c.931G>A	NP_001078895.2:p.Gly311Ser	missense
NM_001085427.3:c.931G>A	NP_001078896.2:p.Gly311Ser	missense
NM_001085428.3:c.673G>A	NP_001078897.1:p.Gly225Ser	missense
NM_001362782.2:c.673G>A	NP_001349711.1:p.Gly225Ser	missense
NC_000022.11:g.50626202C>T
NC_000022.10:g.51064630C>T
NG_009260.2:g.6978G>A

... more HGVS ... less HGVS

Protein change

G311S, G225S

Other names

ARSA, GLY309SER

Canonical SPDI

NC_000022.11:50626201:C:T

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes 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.

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

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA115967 OMIM: 607574.0011 dbSNP: rs74315459 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 8101038 to determine the location of this allele on current reference sequence (G311S).

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.
Metachromatic leukodystrophy, late infantile form	Pathogenic (1)	no assertion criteria provided	Aug 1, 1993	RCV000003206.2
Pseudoarylsulfatase A deficiency	no classifications from unflagged records (1)	no classifications from unflagged records	Jan 31, 2024	RCV000714802.4
Metachromatic leukodystrophy	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Sep 26, 2024	RCV000666302.24
Abnormality of the nervous system	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001813940.1
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV002286693.5

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.
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755533.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV001963619.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021	Sex: male
Pathogenic (Sep 30, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002576955.2 First in ClinVar: Oct 08, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate G309S results in a significant reduction in enzyme activity (Kreysing et al., 1993; Bhringer et al., 2017); Not observed at significant … (more) Published functional studies demonstrate G309S results in a significant reduction in enzyme activity (Kreysing et al., 1993; Bhringer et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.G309S; This variant is associated with the following publications: (PMID: 8101038, 15326627, 33385934, 27289174, 28762252, 33547378, 33855715, 34426522, 33726816, 27535533) (less)
Pathogenic (Feb 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000923448.2 First in ClinVar: Jun 17, 2019 Last updated: Feb 20, 2024	Number of individuals with the variant: 1 Geographic origin: Iran
Pathogenic (Sep 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV005328383.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Clinical Features: Atypical behavior (present) , Parkinsonian disorder (present) , Apraxia (present) , Leukodystrophy (present) , Reduced impulse control (present)
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005092872.3 First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024	Comment: ARSA: PM3:Strong, PM1, PM2, PM5, PS3:Supporting Number of individuals with the variant: 1
Likely pathogenic (Apr 04, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790571.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (5) PubMed: 26462614‚ 24001781‚ 15326627‚ 8101038‚ 15720392
Pathogenic (May 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metachromatic leukodystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429286.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Comment: This variant was identified as homozygous Number of individuals with the variant: 1
Pathogenic (Nov 27, 2023)	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: SCV001198547.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 8101038‚ 26462614‚ 28670130 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 311 of the ARSA protein (p.Gly311Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 311 of the ARSA protein (p.Gly311Ser). This variant is present in population databases (rs74315459, gnomAD 0.01%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 8101038, 26462614, 28670130). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Gly309Ser. ClinVar contains an entry for this variant (Variation ID: 3060). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 8101038). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 01, 1993)	no assertion criteria provided Method: literature only	METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023364.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 8101038 Comment on evidence: Kreysing et al. (1993) described compound heterozygosity for 2 mutant ARSA alleles in a male patient who presented with gait disturbances at the age of … (more) Kreysing et al. (1993) described compound heterozygosity for 2 mutant ARSA alleles in a male patient who presented with gait disturbances at the age of 18 months suggestive of MLD (250100). Subsequently he lost acquired capabilities such as walking and sitting, developed spastic paresis, and finally became bedridden. He showed episodes of pain attacks occurring several times per hour. Electromyelography showed signs of denervation and decreased nerve conduction velocity. Sural nerve biopsy demonstrated metachromatic granules. The patient had residual ARSA activity of about 10%. Fibroblasts of the patient showed significant sulfatide degradation activity exceeding that of adult MLD patients. One of the mutant alleles was a G-to-A transition in exon 5 causing a gly309-to-ser substitution. Transient expression of this allele resulted in only 13% enzyme activity as compared with the normal. The mutant enzyme was correctly targeted to the lysosomes but was unstable. The other allele showed a deletion of C447 in exon 2, causing a frameshift and a premature stop codon at amino acid position 105 (607574.0012). The findings in this patient contrasted with previous results showing that the late infantile type of MLD is always associated with the complete absence of ARSA activity. In this case, the expression of the mutant ARSA protein may have been influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others. (less)
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	Metachromatic leukodystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, Accession: SCV001426665.1 First in ClinVar: Sep 03, 2020 Last updated: Sep 03, 2020	Age: 0-9 years Sex: male
Pathogenic (Jul 03, 2020)	no assertion criteria provided Method: clinical testing	Metachromatic leukodystrophy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002081649.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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: SCV005046510.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Publications: PubMed (5) PubMed: 15326627‚ 32632536‚ 26462614‚ 31922725‚ 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: 0.28% of wild type enzymatic activity
Uncertain significance (Aug 07, 2018)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Pseudoarylsulfatase A deficiency Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845536.1 First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018	Number of individuals with the variant: 1 Sex: male Geographic origin: Iran
click to load more click to collapse
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Published functional studies demonstrate G309S results in a significant reduction in enzyme activity (Kreysing et al., 1993; Bhringer et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.G309S; This variant is associated with the following publications: (PMID: 8101038, 15326627, 33385934, 27289174, 28762252, 33547378, 33855715, 34426522, 33726816, 27535533)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 311 of the ARSA protein (p.Gly311Ser). This variant is present in population databases (rs74315459, gnomAD 0.01%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 8101038, 26462614, 28670130). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Gly309Ser. ClinVar contains an entry for this variant (Variation ID: 3060). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 8101038). For these reasons, this variant has been classified as Pathogenic.

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.
loss_of_function_variant (SO:0002054)	tandem mass spectrometry used to measure enymatic activity Method citation(s): PubMed(1)	0.28% of wild type enzymatic activity	Gelb Laboratory, University of Washington Accession: SCV005046510.1	Publications PubMed (5) Comment: As described in PMID: 37480112, ARSA enzymatic activity of 0 to <2% of wild type is taken as severe and likely contributes to disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.	Trinidad M	Genome biology	2023	PMID: 37480112
Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients.	Beerepoot S	Neurogenetics	2020	PMID: 32632536
Leukocyte and Dried Blood Spot Arylsulfatase A Assay by Tandem Mass Spectrometry.	Hong X	Analytical chemistry	2020	PMID: 31922725
Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations.	Dehghan Manshadi M	Therapeutics and clinical risk management	2017	PMID: 28670130
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.	Cesani M	Human mutation	2016	PMID: 26462614
Sixteen novel mutations in the arylsulfatase A gene causing metachromatic leukodystrophy.	Luzi P	Gene	2013	PMID: 24001781
Missense mutations as a cause of metachromatic leukodystrophy. Degradation of arylsulfatase A in the endoplasmic reticulum.	Poeppel P	The FEBS journal	2005	PMID: 15720392
Novel mutations associated with metachromatic leukodystrophy: phenotype and expression studies in nine Czech and Slovak patients.	Berná L	American journal of medical genetics. Part A	2004	PMID: 15326627
High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy.	Kreysing J	American journal of human genetics	1993	PMID: 8101038

Text-mined citations for rs74315459 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000487.6(ARSA):c.931G>A (p.Gly311Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74315459 ...