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NM_000263.4(NAGLU):c.1946G>A (p.Trp649Ter) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 8, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000817898.9

Allele description [Variation Report for NM_000263.4(NAGLU):c.1946G>A (p.Trp649Ter)]

NM_000263.4(NAGLU):c.1946G>A (p.Trp649Ter)

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.1946G>A (p.Trp649Ter)
HGVS:
  • NC_000017.11:g.42543952G>A
  • NG_011552.1:g.13020G>A
  • NM_000263.4:c.1946G>AMANE SELECT
  • NP_000254.2:p.Trp649Ter
  • NC_000017.10:g.40695970G>A
  • NM_000263.3:c.1946G>A
Protein change:
W649*
Links:
dbSNP: rs527236038
NCBI 1000 Genomes Browser:
rs527236038
Molecular consequence:
  • NM_000263.4:c.1946G>A - nonsense - [Sequence Ontology: SO:0001587]

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
Name:
Charcot-Marie-Tooth disease axonal type 2V
Synonyms:
CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2V; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2V
Identifiers:
MONDO: MONDO:0014665; MedGen: C5569050; Orphanet: 447964; OMIM: 616491

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000958483Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Apr 8, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Genotype-phenotype correspondence in Sanfilippo syndrome type B.

Zhao HG, Aronovich EL, Whitley CB.

Am J Hum Genet. 1998 Jan;62(1):53-63.

PubMed [citation]
PMID:
9443875
PMCID:
PMC1376807

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958483.6

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

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the C-terminus of the NAGLU protein. Other variant(s) that disrupt this region (p.Trp675*, p.Arg674His, p.Arg674Cys, p.Gln706*) have been observed in individuals with NAGLU-related conditions (PMID: 9443875). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change creates a premature translational stop signal (p.Trp649*) in the NAGLU gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the NAGLU protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NAGLU-related conditions. ClinVar contains an entry for this variant (Variation ID: 660650).

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

Last Updated: Sep 29, 2024