Submissions for variant NM_183235.3(RAB27A):c.259G>C (p.Ala87Pro)

dbSNP: rs104894497

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169674	SCV000221209	uncertain significance	not specified	2014-12-15	criteria provided, single submitter	clinical testing	The Ala87Pro variant in RAB27A has been identified in one individual with familial hemophagocytic lymphohistiocytosis who also carried a loss-of-function RAB27A variant in trans (Stadt 2006). Functional studies indicate this variant leads to the disruption of RAB27A binding with UNC13D and in decreased cytolytic activity and inhibited granulation (Cron and Zhang 2013, Abstract). In summary, although this data supports that this variant may be pathogenic, additional studies are needed to fully assess its clinical significance.
GeneDx	RCV000524022	SCV000617810	likely pathogenic	not provided	2021-04-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with decreased binding to Munc13-4 and delayed granzyme B polarization towards the immunologic synapse (Zhang et al., 2016); 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: 16278825, 26597256, 26880764, 18350256, 20370853, 25544030, 32638196)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000006357	SCV000766638	pathogenic	Griscelli syndrome type 2	2024-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 87 of the RAB27A protein (p.Ala87Pro). This variant is present in population databases (rs104894497, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis and Griscelli syndrome (PMID: 16278825, 25544030). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5991). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 16278825, 26880764). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000006357	SCV000026539	pathogenic	Griscelli syndrome type 2	2006-01-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000524022	SCV001808247	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000524022	SCV001974022	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000006357	SCV004099309	likely pathogenic	Griscelli syndrome type 2	2023-10-30	no assertion criteria provided	clinical testing