VCV000559825.6 - ClinVar

NM_000046.5(ARSB):c.923G>A (p.Gly308Glu)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(2)

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000046.5(ARSB):c.923G>A (p.Gly308Glu)

Variation ID: 559825 Accession: VCV000559825.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q14.1 5: 78885803 (GRCh38) [ NCBI UCSC ] 5: 78181626 (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	Aug 24, 2018	Mar 4, 2025	Sep 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000046.5:c.923G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000037.2:p.Gly308Glu	missense
NM_000046.3:c.923G>A
NM_198709.3:c.923G>A	NP_942002.1:p.Gly308Glu	missense
NC_000005.10:g.78885803C>T
NC_000005.9:g.78181626C>T
NG_007089.1:g.105732G>A

... more HGVS ... less HGVS

Protein change

G308E

Other names

p.Gly308Glu

Canonical SPDI

NC_000005.10:78885802:C:T

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

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.

Links

ClinGen: CA360343477 dbSNP: rs1554079333 VarSome

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.
ARSB		-	-	GRCh38 GRCh37	748	1012

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.
Mucopolysaccharidosis type 6	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Sep 20, 2023	RCV000677608.9

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.
Uncertain significance (Jan 01, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Mucopolysaccharidosis type 6 Affected status: yes Allele origin: germline	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova Accession: SCV000803125.1 First in ClinVar: Aug 24, 2018 Last updated: Aug 24, 2018	Publications: PubMed (2) PubMed: 30118150‚ 24798265 Comment: Absent from GnomAD (PM2)

Uncertain significance (Feb 02, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis type 6 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004234509.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024

Likely pathogenic (Sep 09, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis type 6 Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088841.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: This variant was previously reported in compound heterozygous state in a 4years old Syrian patient diagnosed with Mucopolysaccharidosis type VI and it was reported in … (more) This variant was previously reported in compound heterozygous state in a 4years old Syrian patient diagnosed with Mucopolysaccharidosis type VI and it was reported in the literature that this patient showed arylsulphatase B activities far below the reference range and b-galactosidase activity within normal limits, compatible with MPS VI [PMID: 24798265] . In addition, several other exon 5 missense variants p.(Gly303Glu) and p.(Pro313Ala) in the vicinity of identified variant have been previously reported in multiple MPS VI patients and was classified as ‘likely pathogenic’ [PMID: 30118150]. (less)

Pathogenic (Sep 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis type 6 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004293557.2 First in ClinVar: Feb 14, 2024 Last updated: Mar 04, 2025	Publications: PubMed (3) PubMed: 24798265‚ 17643332‚ 18406185 Comment: 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) … (more) 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 ARSB protein function. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 308 of the ARSB protein (p.Gly308Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type VI (PMID: 24798265). ClinVar contains an entry for this variant (Variation ID: 559825). This variant disrupts the p.Gly308 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17643332, 18406185). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This variant was previously reported in compound heterozygous state in a 4years old Syrian patient diagnosed with Mucopolysaccharidosis type VI and it was reported in the literature that this patient showed arylsulphatase B activities far below the reference range and b-galactosidase activity within normal limits, compatible with MPS VI [PMID: 24798265] . In addition, several other exon 5 missense variants p.(Gly303Glu) and p.(Pro313Ala) in the vicinity of identified variant have been previously reported in multiple MPS VI patients and was classified as ‘likely pathogenic’ [PMID: 30118150].

Comment:

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 ARSB protein function. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 308 of the ARSB protein (p.Gly308Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type VI (PMID: 24798265). ClinVar contains an entry for this variant (Variation ID: 559825). This variant disrupts the p.Gly308 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17643332, 18406185). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dried blood spots allow targeted screening to diagnose mucopolysaccharidosis and mucolipidosis.	Cobos PN	JIMD reports	2015	PMID: 24798265
Maroteaux-Lamy syndrome: functional characterization of pathogenic mutations and polymorphisms in the arylsulfatase B gene.	Garrido E	Molecular genetics and metabolism	2008	PMID: 18406185
Identification of the molecular defects in Spanish and Argentinian mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) patients, including 9 novel mutations.	Garrido E	Molecular genetics and metabolism	2007	PMID: 17643332

Text-mined citations for rs1554079333 ...

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 May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000046.5(ARSB):c.923G>A (p.Gly308Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554079333 ...