ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter) (rs775200333)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723878 SCV000331576 pathogenic not provided 2015-12-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000301281 SCV000410795 pathogenic Deficiency of alpha-mannosidase 2017-04-28 criteria provided, single submitter clinical testing The MAN2B1 c.1383C>A (p.Tyr461Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in a total of eight individuals with alpha-mannosidosis (including two sibling pairs) in a compound heterozygous state (Stensland et al 2012; Borgwardt et al. 2015). Control data are not available for this variant, which is reported at a frequency of 0.0001525 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele only in a region of poor sequence coverage. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Tyr461Ter variant is classified as pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000301281 SCV001468285 pathogenic Deficiency of alpha-mannosidase 2020-12-25 criteria provided, single submitter clinical testing Variant summary: MAN2B1 c.1383C>A (p.Tyr461X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.7e-05 in 172302 control chromosomes. c.1383C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis and subsequently cited by others (example, Riise Stensland_2012). These data indicate that the variant is 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. All laboratories classified the variant as pathogenic. One submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000723878 SCV001781059 pathogenic not provided 2020-12-07 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26048034, 22161967, 17979865)

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