NM_000046.5(ARSB):c.1507C>T (p.Gln503Ter) AND Mucopolysaccharidosis type 6

Clinical significance:Likely pathogenic (Last evaluated: Apr 14, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000677494.2

Allele description [Variation Report for NM_000046.5(ARSB):c.1507C>T (p.Gln503Ter)]

NM_000046.5(ARSB):c.1507C>T (p.Gln503Ter)

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.1507C>T (p.Gln503Ter)
HGVS:
  • NC_000005.10:g.78780492G>A
  • NG_007089.1:g.211043C>T
  • NM_000046.5:c.1507C>TMANE SELECT
  • NP_000037.2:p.Gln503Ter
  • NC_000005.9:g.78076315G>A
  • NM_000046.3:c.1507C>T
  • NM_000046.4:c.1507C>T
Protein change:
Q503*
Links:
dbSNP: rs771113472
NCBI 1000 Genomes Browser:
rs771113472
Molecular consequence:
  • NM_000046.5:c.1507C>T - 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
SCV000803004Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padovacriteria provided, single submitter
Likely pathogenic
(Jan 1, 2018)
germlinecuration

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

SCV001572523Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Apr 14, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

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

Evaluation of Aminoglycoside and Non-Aminoglycoside Compounds for Stop-Codon Readthrough Therapy in Four Lysosomal Storage Diseases.

Gómez-Grau M, Garrido E, Cozar M, Rodriguez-Sureda V, Domínguez C, Arenas C, Gatti RA, Cormand B, Grinberg D, Vilageliu L.

PLoS One. 2015;10(8):e0135873. doi: 10.1371/journal.pone.0135873.

PubMed [citation]
PMID:
26287674
PMCID:
PMC4545610
See all PubMed Citations (5)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova, SCV000803004.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

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, SCV001572523.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: ARSB c.1507C>T (p.Gln503X) results in a premature termination codon in the last exon, which is not expected to result in nonsense mediated decay (NMD), but predicted to cause a truncation of the encoded protein, removing 31 amino acids from the encoded protein. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 4e-06 in 251464 control chromosomes (gnomAD). The variant, c.1507C>T, has been reported in the literature in at least one apparently homozygous individual affected with Mucopolysaccharidosis Type VI of intermediate severity (Maroteaux-Lamy Syndrome) (Villani_1999). At least one publication reported greatly decreased enzyme activity, together with high levels of ARSB mRNA in patient derived fibroblast, indicating the lack of NMD (Bartolomeo_2012). One submitter has provided clinical-significance assessments for this variant in 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 likely pathogenic.

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

Last Updated: Nov 27, 2021

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