Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000815106 | SCV000955550 | uncertain significance | Combined immunodeficiency due to LRBA deficiency | 2019-04-18 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs139428686, ExAC 0.005%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with LRBA-related disease. This sequence change replaces arginine with cysteine at codon 2352 of the LRBA protein (p.Arg2352Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. |
Genetic Services Laboratory, |
RCV001816894 | SCV002065748 | uncertain significance | not specified | 2021-12-01 | criteria provided, single submitter | clinical testing | This sequence change does not appear to have been previously described in individuals with LRBA-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.0047% in the non-Finnish European subpopulation (dbSNP rs139428686). The p.Arg2352Cys change affects a highly conserved amino acid residue located in a domain of the LRBA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg2352Cys substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg2352Cys change remains unknown at this time. |