ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.2161G>A (p.Val721Met)

gnomAD frequency: 0.00012  dbSNP: rs148134639
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507951 SCV000604141 uncertain significance not specified 2016-10-12 criteria provided, single submitter clinical testing
Invitae RCV001272185 SCV002114325 uncertain significance Deficiency of alpha-mannosidase 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 721 of the MAN2B1 protein (p.Val721Met). This variant is present in population databases (rs148134639, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 439875). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAN2B1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000507951 SCV003934625 uncertain significance not specified 2023-05-09 criteria provided, single submitter clinical testing Variant summary: MAN2B1 c.2161G>A (p.Val721Met) results in a conservative amino acid change located in the Glycosyl hydrolase family 38, C-terminal (IPR000602) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (0.00012 vs 0.0016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2161G>A in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen RCV003311832 SCV004011019 uncertain significance not provided 2023-06-01 criteria provided, single submitter clinical testing MAN2B1: PP4:Moderate, PM2:Supporting, PM3:Supporting, BP4
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252562 SCV001428319 likely benign Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Natera, Inc. RCV001272185 SCV001453915 uncertain significance Deficiency of alpha-mannosidase 2019-11-11 no assertion criteria provided clinical testing

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