Submissions for variant NM_183235.3(RAB27A):c.220G>C (p.Asp74His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058476	SCV003442951	likely pathogenic	Griscelli syndrome type 2	2023-03-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 2137719). This missense change has been observed in individual(s) with Griscelli syndrome type 2 (PMID: 27016801). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 74 of the RAB27A protein (p.Asp74His). 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. 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. This variant disrupts the p.Asp74 amino acid residue in RAB27A. Other variant(s) that disrupt this residue have been observed in individuals with RAB27A-related conditions (PMID: 22475297), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects RAB27A function (PMID: 27016801).