Submissions for variant NM_000528.4(MAN2B1):c.2401G>T (p.Gly801Cys)

gnomAD frequency: 0.00030  dbSNP: rs142702682

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000660542	SCV000782647	uncertain significance	Deficiency of alpha-mannosidase	2017-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000660542	SCV001287689	uncertain significance	Deficiency of alpha-mannosidase	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000660542	SCV001412173	uncertain significance	Deficiency of alpha-mannosidase	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 801 of the MAN2B1 protein (p.Gly801Cys). This variant is present in population databases (rs142702682, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 547954). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. 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.
Genome-Nilou Lab	RCV000660542	SCV002027037	uncertain significance	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000660542	SCV002775142	uncertain significance	Deficiency of alpha-mannosidase	2022-04-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002532017	SCV003557036	uncertain significance	Inborn genetic diseases	2021-06-04	criteria provided, single submitter	clinical testing	The c.2401G>T (p.G801C) alteration is located in exon 20 (coding exon 20) of the MAN2B1 gene. This alteration results from a G to T substitution at nucleotide position 2401, causing the glycine (G) at amino acid position 801 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003420157	SCV004117187	uncertain significance	MAN2B1-related disorder	2023-05-05	criteria provided, single submitter	clinical testing	The MAN2B1 c.2401G>T variant is predicted to result in the amino acid substitution p.Gly801Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/19-12759985-C-A), which may be too common to be causative. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000660542	SCV002086904	uncertain significance	Deficiency of alpha-mannosidase	2019-11-11	no assertion criteria provided	clinical testing