Submissions for variant NM_000528.4(MAN2B1):c.2426T>C (p.Leu809Pro)

gnomAD frequency: 0.00006  dbSNP: rs80338681

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000020367	SCV000220431	likely pathogenic	Deficiency of alpha-mannosidase	2014-06-19	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020367	SCV000821507	pathogenic	Deficiency of alpha-mannosidase	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 809 of the MAN2B1 protein (p.Leu809Pro). This variant is present in population databases (rs80338681, gnomAD 0.01%). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 9915946, 22161967, 23613340, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21210). 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: 9915946, 15035660). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020367	SCV000919602	pathogenic	Deficiency of alpha-mannosidase	2018-04-05	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.2426T>C (p.Leu809Pro) results in a non-conservative amino acid change located in the glycosyl hydrolase family-38 C-terminal domain (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 6.9e-05 in 277176 control chromosomes (gnomAD and publication controls). This frequency is not higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (6.9e-05 vs 0.0016), allowing no conclusion about variant significance. The variant, c.2426T>C, has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Berg 1999, Borgwardt 2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in <10% of normal activity (Berg 1999, Hansen 2004). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000020367	SCV002014054	pathogenic	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000020367	SCV002499241	pathogenic	Deficiency of alpha-mannosidase	2022-02-02	criteria provided, single submitter	clinical testing	PM3_Strong, PS3, PP3, PM2
Fulgent Genetics, Fulgent Genetics	RCV000020367	SCV002809428	pathogenic	Deficiency of alpha-mannosidase	2021-11-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000020367	SCV003823468	pathogenic	Deficiency of alpha-mannosidase	2022-01-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020367	SCV004191853	pathogenic	Deficiency of alpha-mannosidase	2024-03-25	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020367	SCV000040755	not provided	Deficiency of alpha-mannosidase		no assertion provided	literature only
OMIM	RCV000020367	SCV000056375	pathogenic	Deficiency of alpha-mannosidase	2012-03-01	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000020367	SCV000243994	uncertain significance	Deficiency of alpha-mannosidase	2012-06-07	no assertion criteria provided	literature only
Natera, Inc.	RCV000020367	SCV001461337	pathogenic	Deficiency of alpha-mannosidase	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755744	SCV005350757	pathogenic	MAN2B1-related disorder	2024-08-14	no assertion criteria provided	clinical testing	The MAN2B1 c.2426T>C variant is predicted to result in the amino acid substitution p.Leu809Pro. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with alpha-mannosidosis (see for example Berg. et al. 1999. PubMed ID: 9915946; Borgwardt. et al. 2015. PubMed ID: 26048034). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is interpreted as pathogenic in ClinVar by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/21210/). This variant is interpreted as likely pathogenic.