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

gnomAD frequency: 0.00012  dbSNP: rs148134639

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	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
Ambry Genetics	RCV004023433	SCV004901118	uncertain significance	Inborn genetic diseases	2022-06-17	criteria provided, single submitter	clinical testing	The c.2161G>A (p.V721M) alteration is located in exon 17 (coding exon 17) of the MAN2B1 gene. This alteration results from a G to A substitution at nucleotide position 2161, causing the valine (V) at amino acid position 721 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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