Submissions for variant NM_000528.4(MAN2B1):c.455A>G (p.Asn152Ser)

gnomAD frequency: 0.00088  dbSNP: rs200164758

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000968907	SCV001116391	likely benign	Deficiency of alpha-mannosidase	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000968907	SCV001287904	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.
GeneDx	RCV001766798	SCV001991904	uncertain significance	not provided	2019-04-17	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000968907	SCV002014553	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	RCV004586992	SCV005076095	likely benign	not specified	2024-04-16	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.455A>G (p.Asn152Ser) results in a conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 1613846 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database (v4.0.0) is approximately 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 African or African-American origin. To our knowledge, no occurrence of c.455A>G in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 786791). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000968907	SCV001455947	uncertain significance	Deficiency of alpha-mannosidase	2020-01-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003960802	SCV004775571	likely benign	MAN2B1-related disorder	2023-12-26	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).