ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.1109G>A (p.Trp370Ter) (rs786204715)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169531 SCV000221010 likely pathogenic Deficiency of alpha-mannosidase 2015-01-08 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169531 SCV001337781 pathogenic Deficiency of alpha-mannosidase 2020-01-16 criteria provided, single submitter clinical testing Variant summary: MAN2B1 c.1109G>A (p.Trp370X) 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. This variant also falls at the last nucleotide of exon 8 of the MAN2B1 coding sequence, which is part of the consensus splice site for this exon. Two computational tools predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251334 control chromosomes (gnomAD). The variant, c.1109G>A, has been reported in the literature in two homozygous patients (siblings) affected with Alpha-Mannosidosis (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. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169531 SCV001581392 pathogenic Deficiency of alpha-mannosidase 2020-08-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp370*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mannosidosis (PMID: 22161967). ClinVar contains an entry for this variant (Variation ID: 189118). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). For these reasons, this variant has been classified as Pathogenic.

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