Submissions for variant NM_000528.4(MAN2B1):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00002  dbSNP: rs967834240

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667554	SCV000792026	uncertain significance	Deficiency of alpha-mannosidase	2017-06-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000667554	SCV001281509	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.
Genome-Nilou Lab	RCV000667554	SCV002027043	uncertain significance	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469244	SCV002766068	uncertain significance	not specified	2022-11-08	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (Met24). The variant allele was found at a frequency of 8.9e-05 in 146180 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (8.9e-05 vs 0.0016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1A>G in individuals affected with Alpha-Mannosidosis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667554	SCV003279549	uncertain significance	Deficiency of alpha-mannosidase	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the MAN2B1 mRNA. The next in-frame methionine is located at codon 24. This variant is present in population databases (no rsID available, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 552319). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002530715	SCV003736966	uncertain significance	Inborn genetic diseases	2021-03-26	criteria provided, single submitter	clinical testing	The c.1A>G (p.M1?) alteration is located in coding exon 1 of the MAN2B1 gene and consists of a A to G substitution at nucleotide position 1. This changes the amino acid from a methionine to a (?) at the initiation codon. Sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame and are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003128685	SCV003805891	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge