rs80338680
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The ENST00000456935.7(MAN2B1):c.2248C>T(p.Arg750Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,602,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R750Q) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000456935.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAN2B1 | NM_000528.4 | c.2248C>T | p.Arg750Trp | missense_variant | 18/24 | ENST00000456935.7 | NP_000519.2 | |
MAN2B1 | NM_001173498.2 | c.2245C>T | p.Arg749Trp | missense_variant | 18/24 | NP_001166969.1 | ||
MAN2B1 | XM_005259913.3 | c.2251C>T | p.Arg751Trp | missense_variant | 18/24 | XP_005259970.1 | ||
MAN2B1 | XM_047438841.1 | c.1147C>T | p.Arg383Trp | missense_variant | 11/17 | XP_047294797.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAN2B1 | ENST00000456935.7 | c.2248C>T | p.Arg750Trp | missense_variant | 18/24 | 1 | NM_000528.4 | ENSP00000395473 | A1 | |
MAN2B1 | ENST00000221363.8 | c.2245C>T | p.Arg749Trp | missense_variant | 18/24 | 1 | ENSP00000221363 | P4 | ||
MAN2B1 | ENST00000466794.5 | n.2838C>T | non_coding_transcript_exon_variant | 16/22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000312 AC: 45AN: 144416Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000235 AC: 59AN: 251482Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135916
GnomAD4 exome AF: 0.000158 AC: 230AN: 1457926Hom.: 0 Cov.: 34 AF XY: 0.000160 AC XY: 116AN XY: 725240
GnomAD4 genome AF: 0.000311 AC: 45AN: 144502Hom.: 0 Cov.: 30 AF XY: 0.000343 AC XY: 24AN XY: 70014
ClinVar
Submissions by phenotype
Deficiency of alpha-mannosidase Pathogenic:15Uncertain:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 28, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 29, 2023 | PS3, PM2, PM3_Very Strong, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 04, 2019 | NM_000528.3(MAN2B1):c.2248C>T(R750W) is classified as pathogenic in the context of alpha-mannosidosis. Sources cited for classification include the following: PMID 22161967, 9915946, 23613340, 9758606 and 15035660. Classification of NM_000528.3(MAN2B1):c.2248C>T(R750W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 750 of the MAN2B1 protein (p.Arg750Trp). This variant is present in population databases (rs80338680, gnomAD 0.1%). This missense change has been observed in individuals with MAN2B1-related conditions (PMID: 9758606, 9915946, 22161967). ClinVar contains an entry for this variant (Variation ID: 1687). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 9758606, 15035660). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 07, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with types I and II alpha-mannosidosis (MIM#248500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 83 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 6 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolases family 38 C-terminal domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants reported in individuals with alpha-mannosidosis (ClinVar, PMID: 26048034). (SP) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 16, 2017 | The MAN2B1 c.2248C>T (p.Arg750Trp) missense variant is one of the most frequently reported variants among individuals with alpha-mannosidosis from European populations and generally accounts for more than 27% of all disease alleles in studied cohorts (Malm et al. 2001; Riise Stensland et al. 2012; Borgwardt et al. 2015). Across a selection of the available literature, the p.Arg750Trp variant has been identified in at least 50 individuals with alpha-mannosidosis, including 22 individuals in a homozygous state and 28 individuals in a compound heterozygous state (Gotoda et al. 1998; Berg et al. 1999; Riise Stensland et al. 2012; Borgwardt et al. 2015). The p.Arg750Trp variant was absent from at least 236 control alleles but is reported at a frequency of 0.001361 in the European (Finnish) population of the Exome Aggregation Consortium. The activity of alpha mannosidase in fibroblasts of two unrelated patients has been reported to demonstrate two percent activity of normal (Gotoda et al. 1998). Nearly absent enzyme activity due to misfolded protein arrested in the endoplasmic reticulum as inactive single-chain forms has been demonstrated in COS1 and COS7 cells transfected with the p.Arg750Trp variant (Gotoda et al. 1998; Hansen et al. 2004). The p.Arg750Trp variant has been used as a negative control for functional analysis of novel MAN2B1 variants (Borgwardt et al. 2015). Based on the collective evidence, the p.Arg750Trp 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 30, 2019 | This variant was identified as homozygous - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2017 | Variant summary: The MAN2B1 c.2248C>T (p.Arg750Trp) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 28/121552 control chromosomes at a frequency of 0.0002304, which does not exceed the estimated maximal expected allele frequency of a pathogenic MAN2B1 variant (0.0015811). The variant has been reported in numerous affected individuals in the literature, both in the homozgyous and compound heterozygous state. Additionally, a functional study showed that the variant protein was misfolded and arrested in the ER as inactive single-chain form, and patients and transfected cell lines both had almost no detectable enzyme activity (Gotoda_1998, Hansen_2004). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 19, 2020 | The p.Arg750Trp variant in MAN2B1 has been reported in the homozygous or compound heterozygous state in >50 individuals with alpha-mannosidosis and segregated with disease in at least 5 affected individuals from 5 families (Berg 1999 PMID: 9915946, Lehalle 2019 PMID: 31241255, Gotoda 1998 PMID: 9758606, Riise Stensland 2012 PMID: 22161967, Gotoda 1998 PMID: 9758606). It has also been identified in 0.12% (29/25036) of Finnish chromosomes and 0.04% (48/128844) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg750Trp variant has also been reported in ClinVar (Variation ID 1687). Computational prediction tools and conservation analyses are consistent with pathogenicity. In vitro functional studies support that this variant impacts protein function (Hansen 2004 PMID: 15035660, Khan 2009 PMID: 19958498). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha-mannosidosis. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PP3, PS3_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 25, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 15, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19958498, 18651971, 16919251, 34429528, 15035660, 9758606, 26048034, 9915946, 34426522, 31589614, 31241255, 30548430, 31980526, 35242565, 35314707, 32531858, 37791705, 22161967) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MAN2B1: PM3:Very Strong, PM2, PP4:Moderate, PS3:Supporting - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at