Submissions for variant NM_000528.4(MAN2B1):c.2782G>C (p.Gly928Arg)

gnomAD frequency: 0.00006  dbSNP: rs754733253

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000358688	SCV000341394	likely benign	not specified	2016-04-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000415194	SCV000794526	uncertain significance	Deficiency of alpha-mannosidase	2017-09-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000415194	SCV001051716	likely benign	Deficiency of alpha-mannosidase	2024-01-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000415194	SCV002014524	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	RCV000358688	SCV002556069	likely benign	not specified	2022-06-22	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.2782G>C (p.Gly928Arg) results in a non-conservative amino acid change located in the glycosyl hydrolases family 38, C-terminal beta sandwich domain (IPR041147) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251214 control chromosomes (gnomAD), predominantly at a frequency of 0.0026 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (0.0016), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.2782G>C in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as likely benign, one as benign, and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV000415194	SCV000328771	uncertain significance	Deficiency of alpha-mannosidase	2014-10-03	no assertion criteria provided	clinical testing	Our laboratory reported dual molecular diagnoses in SCN8A (NM_014191.3, c.647T>G) and MAN2B1 (NM_000528.3, c.2782G>C and c.1383C>G in trans) in one individual with reported features that include delayed motor milestones, delayed speech, intellectual disability, hypotonia, seizure disorder (refractory epilepsy), abnormal movements (dyskinesia), minor dysmorphic features (flat nasal bridge, prominent eyes, full lips), microcephaly, dysphagia, and cortical visual impairment. Heterozygotes for the MAN2B1 variants would be expected to be asymptomatic carriers.
Natera, Inc.	RCV000415194	SCV002086893	benign	Deficiency of alpha-mannosidase	2020-01-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755844	SCV005363888	likely benign	MAN2B1-related disorder	2024-09-25	no assertion criteria provided	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).