ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.2426T>C (p.Leu809Pro) (rs80338681)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020367 SCV000220431 likely pathogenic Deficiency of alpha-mannosidase 2014-06-19 criteria provided, single submitter literature only
Invitae RCV000020367 SCV000821507 pathogenic Deficiency of alpha-mannosidase 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 809 of the MAN2B1 protein (p.Leu809Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs80338681, ExAC 0.02%). This variant has been reported in individuals affected with alpha-mannosidosis (PMID: 9915946, 22161967, 23613340, 26048034). ClinVar contains an entry for this variant (Variation ID: 21210). Experimental studies have shown that this missense changes disrupts MAN2B1 protein processing and secretion, resulting in reduced enzymatic activity (PMID: 9915946, 15035660). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020367 SCV000919602 pathogenic Deficiency of alpha-mannosidase 2018-04-05 criteria provided, single submitter clinical testing Variant summary: MAN2B1 c.2426T>C (p.Leu809Pro) results in a non-conservative amino acid change located in the glycosyl hydrolase family-38 C-terminal domain (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 6.9e-05 in 277176 control chromosomes (gnomAD and publication controls). This frequency is not higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (6.9e-05 vs 0.0016), allowing no conclusion about variant significance. The variant, c.2426T>C, has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Berg 1999, Borgwardt 2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <10% of normal activity (Berg 1999, Hansen 2004). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000020367 SCV000040755 pathologic Deficiency of alpha-mannosidase 2012-05-03 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000020367 SCV000056375 pathogenic Deficiency of alpha-mannosidase 2012-03-01 no assertion criteria provided literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000020367 SCV000243994 uncertain significance Deficiency of alpha-mannosidase 2012-06-07 no assertion criteria provided literature only
Natera, Inc. RCV000020367 SCV001461337 pathogenic Deficiency of alpha-mannosidase 2020-09-16 no assertion criteria provided clinical testing

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