Submissions for variant NM_000528.4(MAN2B1):c.2248C>T (p.Arg750Trp)

dbSNP: rs80338680

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001755	SCV000697259	pathogenic	Deficiency of alpha-mannosidase	2017-05-26	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000622985	SCV000741126	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001755	SCV000914830	pathogenic	Deficiency of alpha-mannosidase	2017-08-16	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000001755	SCV000953586	pathogenic	Deficiency of alpha-mannosidase	2024-01-16	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000001755	SCV001163443	pathogenic	Deficiency of alpha-mannosidase		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000001755	SCV001193961	pathogenic	Deficiency of alpha-mannosidase	2019-12-04	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV001091771	SCV001247979	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MAN2B1: PM3:Very Strong, PM2, PP4:Moderate, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000001755	SCV001429406	pathogenic	Deficiency of alpha-mannosidase	2019-01-30	criteria provided, single submitter	clinical testing	This variant was identified as homozygous
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001091771	SCV001446925	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000001755	SCV001653107	pathogenic	Deficiency of alpha-mannosidase	2020-05-19	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001091771	SCV001782377	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R750W impairs enzyme activity and is damaging to protein function in vitro (Gotoda et al., 1998; Hansen et al., 2004); 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, 15035660, 9758606, 26048034, 9915946, 34426522, 31589614, 31241255, 30548430, 31980526, 22161967)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001091771	SCV002009122	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000001755	SCV002014154	pathogenic	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000001755	SCV002581004	pathogenic	Deficiency of alpha-mannosidase	2022-06-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001755	SCV002767249	pathogenic	Deficiency of alpha-mannosidase	2022-02-02	criteria provided, single submitter	clinical testing	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) 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
Fulgent Genetics, Fulgent Genetics	RCV000001755	SCV002795772	pathogenic	Deficiency of alpha-mannosidase	2021-08-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000001755	SCV004237920	pathogenic	Deficiency of alpha-mannosidase	2023-05-16	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000001755	SCV004244519	pathogenic	Deficiency of alpha-mannosidase	2023-11-29	criteria provided, single submitter	clinical testing	PS3, PM2, PM3_Very Strong, PP3
OMIM	RCV000001755	SCV000021911	pathogenic	Deficiency of alpha-mannosidase	2012-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000001755	SCV000040754	not provided	Deficiency of alpha-mannosidase		no assertion provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000001755	SCV000243990	uncertain significance	Deficiency of alpha-mannosidase	2012-06-07	no assertion criteria provided	literature only
Natera, Inc.	RCV000001755	SCV001454352	pathogenic	Deficiency of alpha-mannosidase	2020-09-16	no assertion criteria provided	clinical testing