NM_000046.5(ARSB):c.438G>A (p.Trp146Ter) AND Mucopolysaccharidosis type 6

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 26, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000677566.3

Allele description [Variation Report for NM_000046.5(ARSB):c.438G>A (p.Trp146Ter)]

NM_000046.5(ARSB):c.438G>A (p.Trp146Ter)

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.438G>A (p.Trp146Ter)
HGVS:
  • NC_000005.10:g.78969067C>T
  • NG_007089.1:g.22468G>A
  • NM_000046.5:c.438G>AMANE SELECT
  • NM_198709.3:c.438G>A
  • NP_000037.2:p.Trp146Ter
  • NP_942002.1:p.Trp146Ter
  • NC_000005.9:g.78264890C>T
  • NM_000046.3:c.438G>A
  • NM_000046.4:c.438G>A
Protein change:
W146*
Links:
dbSNP: rs757061042
NCBI 1000 Genomes Browser:
rs757061042
Molecular consequence:
  • NM_000046.5:c.438G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_198709.3:c.438G>A - nonsense - [Sequence Ontology: SO:0001587]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000803079Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padovacriteria provided, single submitter
Likely pathogenic
(Jan 1, 2018)
germlinecuration

PubMed (5)
[See all records that cite these PMIDs]

SCV001442541Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 12, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001579934Invitaecriteria provided, single submitter
Pathogenic
(Oct 26, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedcuration

Citations

PubMed

[Identification of mutations in the arylsulfatase B gene in Russian mucopolysaccharidosis type VI patients].

Voskoboeva EIu, Krasnopol'skaia KD, Peters K, von Figura K.

Genetika. 2000 Jun;36(6):837-43. Russian.

PubMed [citation]
PMID:
10923267

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (7)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova, SCV000803079.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (5)

Description

Nonsense variant (PVS1); Very low frequency in ExAc (PM2)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442541.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: ARSB c.438G>A (p.Trp146X) 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 4e-06 in 251470 control chromosomes. c.438G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Karageorgos_2007, Thumler_2012, Tomanin_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001579934.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Trp146*) 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 not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871). ClinVar contains an entry for this variant (Variation ID: 559787). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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