Submissions for variant NM_005908.4(MANBA):c.1922G>A (p.Arg641His)

gnomAD frequency: 0.00006  dbSNP: rs569997475

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001786457	SCV002028743	likely pathogenic	not provided	2024-08-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced secreted protein expression and significantly decreased enzyme activity compared to wild-type (PMID: 19728872, 30552791); 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: 22369051, 18980795, 30552791, 19728872, 30548430)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001264746	SCV002150396	uncertain significance	Beta-D-mannosidosis	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 641 of the MANBA protein (p.Arg641His). This variant is present in population databases (rs569997475, gnomAD 0.05%). This missense change has been observed in individual(s) with beta-mannosidosis (PMID: 18980795). ClinVar contains an entry for this variant (Variation ID: 975740). Invitae Evidence 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 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 MANBA protein function. Experimental studies have shown that this missense change affects MANBA function (PMID: 19728872, 30552791). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264746	SCV005380543	likely pathogenic	Beta-D-mannosidosis	2024-08-20	criteria provided, single submitter	clinical testing	Variant summary: MANBA c.1922G>A (p.Arg641His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251248 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MANBA causing Beta-Mannosidosis (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.1922G>A has been reported in the literature in at-least one homozygous individual affected with Beta-Mannosidosis (example: Labauge_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in eukaryotic cells (Sabourdy_2009). The following publications have been ascertained in the context of this evaluation (PMID: 22369051, 18980795, 19728872). ClinVar contains an entry for this variant (Variation ID: 975740). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001264746	SCV005659884	uncertain significance	Beta-D-mannosidosis	2024-01-19	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252566	SCV001428324	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264746	SCV001442980	likely pathogenic	Beta-D-mannosidosis	2020-04-22	no assertion criteria provided	clinical testing
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004570645	SCV005049952	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research