NM_000263.4(NAGLU):c.1694G>T (p.Arg565Leu) AND Mucopolysaccharidosis, MPS-III-B

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 13, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000673096.2

Allele description [Variation Report for NM_000263.4(NAGLU):c.1694G>T (p.Arg565Leu)]

NM_000263.4(NAGLU):c.1694G>T (p.Arg565Leu)

Gene:
NAGLU:N-acetyl-alpha-glucosaminidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.2
Genomic location:
Preferred name:
NM_000263.4(NAGLU):c.1694G>T (p.Arg565Leu)
HGVS:
  • NC_000017.11:g.42543700G>T
  • NG_011552.1:g.12768G>T
  • NM_000263.4:c.1694G>TMANE SELECT
  • NP_000254.2:p.Arg565Leu
  • NC_000017.10:g.40695718G>T
  • NM_000263.3:c.1694G>T
Protein change:
R565L
Links:
dbSNP: rs104894598
NCBI 1000 Genomes Browser:
rs104894598
Molecular consequence:
  • NM_000263.4:c.1694G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mucopolysaccharidosis, MPS-III-B (MPS3B)
Synonyms:
NAGLU DEFICIENCY; Mucopoly-saccharidosis type 3B; Sanfilippo syndrome B; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009656; MedGen: C0086648; OMIM: 252920

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000798264Counsylcriteria provided, single submitter
Uncertain significance
(Mar 2, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001983439Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 13, 2021)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Biochemical, machine learning and molecular approaches for the differential diagnosis of Mucopolysaccharidoses.

Kadali S, Naushad SM, Radha Rama Devi A, Bodiga VL.

Mol Cell Biochem. 2019 Aug;458(1-2):27-37. doi: 10.1007/s11010-019-03527-6. Epub 2019 Mar 21.

PubMed [citation]
PMID:
30903511

Prevalence and Novel Mutations of Lysosomal Storage Disorders in United Arab Emirates : LSD in UAE.

Al-Jasmi FA, Tawfig N, Berniah A, Ali BR, Taleb M, Hertecant JL, Bastaki F, Souid AK.

JIMD Rep. 2013;10:1-9. doi: 10.1007/8904_2012_182. Epub 2013 Jan 1.

PubMed [citation]
PMID:
23430803
PMCID:
PMC3755583

Details of each submission

From Counsyl, SCV000798264.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983439.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: NAGLU c.1694G>T (p.Arg565Leu) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal (IPR024732) 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 1.2e-05 in 248730 control chromosomes. c.1694G>T has been reported in the literature in multiple individuals from one family affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and has been subsequently cited by others (example, Al-Jasmi_2013, Kadali_2019). Moreover, other missense variants located at the same codon (p.Arg565Gln, p.Arg565Trp and p.Arg565Pro) have been reported in patients with Sanfilippo Syndrome B suggesting the critical relevance of Arginine 565 residue to protein function. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. 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

Last Updated: Oct 30, 2021

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