Submissions for variant NM_000528.4(MAN2B1):c.1068C>G (p.Pro356=)

gnomAD frequency: 0.00217  dbSNP: rs117880912

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000402847	SCV000410800	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780389	SCV000917599	benign	not specified	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.1068C>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0035 in 277160 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 2-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1068C>G in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) and another clinical diagnostic laboratory (EGL) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000402847	SCV001102341	benign	Deficiency of alpha-mannosidase	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000402847	SCV001737301	benign	Deficiency of alpha-mannosidase	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000675483	SCV001896084	benign	not provided	2019-08-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000675483	SCV004137898	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MAN2B1: BP4, BP7, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV000675483	SCV000801173	likely benign	not provided	2015-12-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000402847	SCV001454356	benign	Deficiency of alpha-mannosidase	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000780389	SCV001925822	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000675483	SCV001964384	likely benign	not provided		no assertion criteria provided	clinical testing