NM_005908.4(MANBA):c.1622G>A (p.Trp541Ter) AND Beta-D-mannosidosis

Clinical significance:Likely pathogenic

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001356140.1

Allele description [Variation Report for NM_005908.4(MANBA):c.1622G>A (p.Trp541Ter)]

NM_005908.4(MANBA):c.1622G>A (p.Trp541Ter)

Gene:
MANBA:mannosidase beta [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q24
Genomic location:
Preferred name:
NM_005908.4(MANBA):c.1622G>A (p.Trp541Ter)
HGVS:
  • NC_000004.12:g.102657764C>T
  • NG_012804.1:g.108231G>A
  • NG_012804.2:g.108231G>A
  • NM_005908.4:c.1622G>AMANE SELECT
  • NP_005899.3:p.Trp541Ter
  • NC_000004.11:g.103578921C>T
Protein change:
W541*
Links:
dbSNP: rs771865668
NCBI 1000 Genomes Browser:
rs771865668
Molecular consequence:
  • NM_005908.4:c.1622G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Beta-D-mannosidosis (MANSB)
Synonyms:
Mannosidosis, beta A, lysosomal; Lysosomal beta-mannosidase deficiency; Beta-mannosidase deficiency
Identifiers:
MONDO: MONDO:0009562; MedGen: C4048196; Orphanet: 118; OMIM: 248510

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001551214Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedLikely pathogenicunknownclinical testing

Summary from all submissions

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

Details of each submission

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551214.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

MANBA, c.1622G>A, p.Trp541*, Heterozygous, Likely PathogenicVariant Interpretation: The p.Trp541* variant was not identified in the literature, nor was it identified in the LOVD 3.0 database. The variant was identified in ClinVar (Pathogenic, 1 submitter, classified as pathogenic by EGL Genetic Diagnostics in 2018) and dbSNP (rs771865668, Pathogenic) databases. The variant was identified in control databases in 2 of 251320 chromosomes at a frequency of 0.000007958 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2 of 113668 chromosomes (freq: 0.000018), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.1622G>A variant leads to a premature stop codon at position 541 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MANBA gene are an established mechanism of disease in beta-mannosidosis and is the type of variant expected to cause the disorder. In summary, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.Disease Information: Homozygous and compound heterozygous pathogenic variants in the MANBA gene cause beta-mannosidosis (OMIM: 248510). Beta-mannosidosis is an autosomal recessive lysosomal sotorage disease of glycoprotein caused by a deficiency of lysosomal beta-mannosidase activity (Verbatim, OMIM: 248510). Phenotypic variability is possible. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (Verbatim, OMIM: 248510). Clinical features include intellectual disability, speech impairment, hypotonia, seizures (rare), and progressive demyelinating peripheral neuropathy. Laboratory anomalies include decreased beta-mannosidase activity in plasma, fibroblasts and leukocytes, and increased urinary disaccharides. Familial Risk: Classic beta-mannosidosis is inherited in an autosomal recessive manner. At conception, the siblings of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. Carrier testing for at-risk relatives at increased risk is possible if the pathogenic variants in the family are known.

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

Last Updated: Nov 27, 2021

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