ClinVar Miner

Submissions for variant NM_005908.4(MANBA):c.1622G>A (p.Trp541Ter) (rs771865668)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000729716 SCV000857402 pathogenic not provided 2017-10-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356140 SCV001551214 likely pathogenic Beta-D-mannosidosis no assertion criteria provided clinical testing 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.

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