ClinVar Miner

Submissions for variant NM_183235.3(RAB27A):c.476A>G (p.Tyr159Cys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003041238 SCV003443587 likely pathogenic Griscelli syndrome type 2 2023-12-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 159 of the RAB27A protein (p.Tyr159Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 25312756, 32542393; Invitae). ClinVar contains an entry for this variant (Variation ID: 2137716). 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%. This variant disrupts the p.Tyr159 amino acid residue in RAB27A. Other variant(s) that disrupt this residue have been observed in individuals with RAB27A-related conditions (PMID: 25312756, 32860008), which suggests that this may be a clinically significant amino acid residue. 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.

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