ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001755 SCV000485236 pathogenic Deficiency of alpha-mannosidase 2015-11-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
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 2018-09-19 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.
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

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