ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.2248C>T (p.Arg750Trp) (rs80338680)

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Total submissions: 15
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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 Clinical Services Laboratory,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 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 750 of the MAN2B1 protein (p.Arg750Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs80338680, ExAC 0.1%). This variant has been observed in numerous individuals and families affected with MAN2B1-related conditions (PMID: 9758606, 9915946, 22161967). ClinVar contains an entry for this variant (Variation ID: 1687). Experimental studies have shown that this missense change has a deleterious effect on protein 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 Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV001091771 SCV001247979 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
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, Partners HealthCare 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 ( 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 2020-09-18 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) This variant is associated with the following publications: (PMID: 31980526, 31241255, 30548430, 9915946, 26048034, 22161967, 9758606, 16919251, 18651971, 19958498, 15035660)
OMIM RCV000001755 SCV000021911 pathogenic Deficiency of alpha-mannosidase 2012-03-01 no assertion criteria provided literature only
GeneReviews RCV000001755 SCV000040754 pathologic Deficiency of alpha-mannosidase 2012-05-03 no assertion criteria provided curation Converted during submission to Pathogenic.
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

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