ClinVar Genomic variation as it relates to human health

Variant summary: RAB27A c.244C>T (p.Arg82Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250912 control chromosomes. c.244C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals reported with features of hemophagocytic lymphohistiocytosis (pHLH) or autosomal recessive Griscelli Syndrome type 2 (GS2) that can progress to HLH (example, Netter_2016, Jin_2018, Gadoury-Levesque_2020, Zhang_2020). At-least one of these publications reported two presumably unaffected homozygous siblings within a family with normal NK cell numbers but reduced CD107a mobilization, which could explain the severely decreased cytotoxic NK cell function (Netter_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating an inhibition in interaction of Rab27a with Munc13-4, but only partially effect on binding of Rab27a to melanophilin (Netter_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=2; VUS, n=1; pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evalution. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 82 of the RAB27A protein (p.Arg82Cys). This variant is present in population databases (rs753966933, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Griscelli syndrome and/or hemophagocytic lymphohistiocytosis (PMID: 27016801, 29357941, 32542393, 32856792, 32888943, 34329649; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 419794). 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) performed at Invitae indicates that this missense variant is expected to disrupt RAB27A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAB27A function (PMID: 27016801). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant has also been observed in the homozygous state in clinically unaffected relatives of affected probands (PMID: 32856792); Reported to be a founder variant in the Qatari population (PMID: 32856792); Published functional studies demonstrate that p.(R82C) impairs NK cell mediated cytotoxicity and impairs the functional activity of the RAB27A protein (PMID: 27016801, 29291352); 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: 30671214, 29357941, 29291352, 31989587, 31388699, 32542393, 31216405, 30919572, 31589614, 32888943, 34054914, 27016801, 34329649, 32856792)

The RAB27A c.244C>T variant is predicted to result in the amino acid substitution p.Arg82Cys. This variant has been reported in the homozygous state in individuals with autosomal recessive Griscelli syndrome, and both segregation data and functional studies support its pathogenicity (Jin et al. 2018. PubMed ID: 29357941; Gadoury-Levesque et al. 2020. PubMed ID: 32542393; Al-Sulaiman et al. 2020. PubMed ID: 32856792; Human Gene Mutation Database). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.