NM_000046.5(ARSB):c.215T>G (p.Leu72Arg) AND Mucopolysaccharidosis type 6

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 2, 2024
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:: RCV000677516.14

Allele description

NM_000046.5(ARSB):c.215T>G (p.Leu72Arg)

Genes:

LOC129994126:ATAC-STARR-seq lymphoblastoid silent region 16127 [Gene]
ARSB:arylsulfatase B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q14.1

Genomic location:

Preferred name:

NM_000046.5(ARSB):c.215T>G (p.Leu72Arg)

HGVS:

NC_000005.10:g.78985034A>C
NG_007089.1:g.6501T>G
NM_000046.5:c.215T>GMANE SELECT
NM_198709.3:c.215T>G
NP_000037.2:p.Leu72Arg
NP_942002.1:p.Leu72Arg
NC_000005.9:g.78280857A>C
NM_000046.3:c.215T>G
NM_000046.4:c.215T>G

Protein change:

L72R

Links:

dbSNP: rs397514441

NCBI 1000 Genomes Browser:

rs397514441

Molecular consequence:

NM_000046.5:c.215T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198709.3:c.215T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis type 6 (MPS6)
Synonyms:: MPS VI; Mucopolysaccharidosis type VI; MPS 6; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009661; MedGen: C0026709; Orphanet: 583; OMIM: 253200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000803026	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2018)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 17458871, 17161971, 25190157, 16435196, 25741868, 30118150
SCV000955328	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16435196, 17458871, 25190157, 28492532
SCV001370604	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 7, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17458871, 16435196, 30118150 Citation Link,
SCV001457630	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002785020	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 12, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003817884	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004209214	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 2, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy.

Karageorgos L, Brooks DA, Harmatz P, Ketteridge D, Pollard A, Melville EL, Parkinson-Lawrence E, Clements PR, Hopwood JJ.

Mol Genet Metab. 2007 Feb;90(2):164-70. Epub 2006 Dec 11.

PubMed [citation]

PMID:: 17161971

[Analysis of clinical features and arylsulfatase B gene mutation in thirteen Chinese children with mucopolysaccharidosis type VI].

Zheng J, Huang Y, Zhao X, Sheng H, Cheng J, Zhou Z, Li X, Mao X, Liu L.

Zhonghua Er Ke Za Zhi. 2014 Jun;52(6):403-8. Chinese.

PubMed [citation]

PMID:: 25190157

See all PubMed Citations (7)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV000803026.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2); Reputable source identifies as pathogenic (PP5)

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

From Invitae, SCV000955328.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 72 of the ARSB protein (p.Leu72Arg). 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 missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 16435196, 17458871, 25190157; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 559740). 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 with a positive predictive value of 95%. For these reasons, this variant has been 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370604.1

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

Description

Variant summary: ARSB c.215T>G (p.Leu72Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182450 control chromosomes. c.215T>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) with early onset and classical, rapidly progressing disease phenotype in the homozygotes (Petry_2005, Karageorgos_2007). These data indicate that the variant is very likely to be associated with disease. One of these publications also reported very low or undetectable ASB protein levels and undetectable enzymatic activities in skin fibroblasts derived from homozygous patients (Karageorgos_2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. 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 Natera, Inc., SCV001457630.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002785020.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003817884.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004209214.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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