Submissions for variant NM_000528.4(MAN2B1):c.222C>A (p.Asp74Glu)

gnomAD frequency: 0.00001  dbSNP: rs746702002

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001572479	SCV001797127	pathogenic	not provided	2020-06-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (absent alpha-mannosidase activity) (Riise Stensland et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22161967, 21505070)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206959	SCV003922717	likely pathogenic	Deficiency of alpha-mannosidase	2023-03-16	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.222C>A (p.Asp74Glu) results in a conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251662 control chromosomes (gnomAD and publication data). c.222C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis or suspected mitochondrial disorders (Riise Stensland_2012, Lieber_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies reported this variant has dramatically reduced alpha-mannosidase activity in transfected cells and was both proteolytically processed and extracellularly secreted, but less efficiently than the wild-type (Kuokkanen_2011, Riise Stensland_2012, Riise Stensland_2015). One ClinVar submitter (evaluation after 2014) cites this variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000206959	SCV004191875	likely pathogenic	Deficiency of alpha-mannosidase	2023-07-07	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000206959	SCV000243956	uncertain significance	Deficiency of alpha-mannosidase	2012-06-07	no assertion criteria provided	literature only