Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Breda Genetics srl | RCV001265535 | SCV001443675 | uncertain significance | Beta-D-mannosidosis | 2020-09-01 | criteria provided, single submitter | clinical testing | The variant c.545G>A (p.Arg182Gln) in MANBA is reported with an estimated allele frequency of 0.00001193 in gnomAD exomes and 0.00003185 in gnomAD genomes, with no homozygous individuals reported. The nucleotide position is conserved across 35 mammalian species (GERP RS: 4.33). In silico analysis indicates that the variant might be damaging. Another pathogenic missense variant, (c.544C>T, p.Arg182Trp) affecting the same amino acid position, has been reported by Gort et al. (2006) in a 24-year-old Spanish woman with mild beta-mannosidosis, showing angiokeratoma corporis, slight deafness, and abdominal pain and no neurological involvement (PMID: 16904924). Based on ACMG variant interpretation guidelines, we classify this variant as uncertain. However, based on the aforementioned evidence, there is a given likelihood that the variant may actually be pathogenic, even if we cannot exclude that it is a rare benign variant. |
| Invitae | RCV001265535 | SCV003447835 | uncertain significance | Beta-D-mannosidosis | 2022-03-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the MANBA protein (p.Arg182Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MANBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 984911). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. |