NM_000046.5(ARSB):c.478C>T (p.Arg160Ter) AND Mucopolysaccharidosis type 6

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 7, 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:: RCV000656129.10

Allele description [Variation Report for NM_000046.5(ARSB):c.478C>T (p.Arg160Ter)]

NM_000046.5(ARSB):c.478C>T (p.Arg160Ter)

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.478C>T (p.Arg160Ter)

HGVS:

NC_000005.10:g.78969027G>A
NG_007089.1:g.22508C>T
NM_000046.5:c.478C>TMANE SELECT
NM_198709.3:c.478C>T
NP_000037.2:p.Arg160Ter
NP_942002.1:p.Arg160Ter
NC_000005.9:g.78264850G>A
NM_000046.3:c.478C>T
NM_000046.4:c.478C>T

Protein change:

R160*

Links:

dbSNP: rs1255777033

NCBI 1000 Genomes Browser:

rs1255777033

Molecular consequence:

NM_000046.5:c.478C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198709.3:c.478C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000609483	Medical Molecular Genetics Department, National Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 1, 2015)	germline	research	PubMed (2) [See all records that cite these PMIDs] 8125475, 25741868
SCV000803083	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2018)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 22441840, 24373060, 17458871, 28884960, 17643332, 25741868, 30118150
SCV002240372	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17458871, 22133300, 8125475, 33163362, 28492532
SCV002511470	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 11, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17458871, 17643332, 24221504, 8125475, 24373060, 22133300 Citation Link,
SCV004209069	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 7, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005087214	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30118150, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing, research, 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

Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: a case series.

Thümler A, Miebach E, Lampe C, Pitz S, Kamin W, Kampmann C, Link B, Mengel E.

J Inherit Metab Dis. 2012 Nov;35(6):1071-9. doi: 10.1007/s10545-012-9474-1. Epub 2012 Mar 23.

PubMed [citation]

PMID:: 22441840

Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey.

Kılıç M, Dursun A, Coşkun T, Tokatlı A, Özgül RK, Yücel-Yılmaz D, Karaca M, Doğru D, Alehan D, Kadayıfçılar S, Genç A, Turan-Dizdar H, Gönüldaş B, Savcı S, Sağlam M, Aksoy C, Arslan U, Sivri HS.

Am J Med Genet A. 2017 Nov;173(11):2954-2967. doi: 10.1002/ajmg.a.38459. Epub 2017 Sep 8.

PubMed [citation]

PMID:: 28884960

See all PubMed Citations (12)

Details of each submission

From Medical Molecular Genetics Department, National Research Center, SCV000609483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	research	PubMed (2)

#	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		4	not provided	not provided	not provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV000803083.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

Description

Nonsense variant (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002240372.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg160*) in the ARSB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSB are known to be pathogenic (PMID: 17458871, 22133300). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ARSB-related conditions (PMID: 8125475, 33163362). ClinVar contains an entry for this variant (Variation ID: 445291). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, SCV002511470.1

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

Description

Variant summary: ARSB c.478C>T (p.Arg160X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251472 control chromosomes. c.478C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Garrido_2007, Jurecka_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as 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 Baylor Genetics, SCV004209069.2

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005087214.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis type VI (Maroteaux-Lamy) (MIM#253200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Age of onset, rate of disease progression, and clinical manifestations vary widely among individuals (PMID: 30118150). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 5 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in ClinVar and detected in multiple families with Maroteaux-Lamy syndrome (MPS VI). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis in an external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: Sep 29, 2024

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