Submissions for variant NM_000528.4(MAN2B1):c.2260G>A (p.Glu754Lys)

gnomAD frequency: 0.00132  dbSNP: rs141212446

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000267336	SCV000410783	uncertain significance	Deficiency of alpha-mannosidase	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000675478	SCV000709515	uncertain significance	not provided	2017-06-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000675478	SCV000801167	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	BS1
Invitae	RCV000267336	SCV001033169	likely benign	Deficiency of alpha-mannosidase	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000675478	SCV001151679	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	MAN2B1: BP4
Genome-Nilou Lab	RCV000267336	SCV002014532	likely benign	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488545	SCV004241901	likely benign	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.2260G>A (p.Glu754Lys) results in a conservative amino acid change located in the Glycosyl hydrolase family 38, C-terminal (IPR011682) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251484 control chromosomes, predominantly at a frequency of 0.0019 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2260G>A in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003940305	SCV004747258	likely benign	MAN2B1-related disorder	2023-07-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000267336	SCV001453914	benign	Deficiency of alpha-mannosidase	2019-11-11	no assertion criteria provided	clinical testing