ClinVar Miner

Submissions for variant NM_004580.4(RAB27A):c.259G>C (p.Ala87Pro) (rs104894497)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000524022 SCV000617810 likely pathogenic not provided 2017-08-07 criteria provided, single submitter clinical testing The A87P variant in the RAB27A gene has been reported in the literature in the presence of a second RAB27A alteration, including a frameshift variant and an intragenic deletion, in individuals with Griscelli syndrome type 2 (Zur et al., 2006; Henkes et al., 2015). The A87P variant was also identified in a sixty-year old male patient with fatal H1N1 influenza who was also identified with variants in the PRF1 and MEFV genes (Schulert et al., 2016). Although not reported in the homozygous state, the A87P variant is observed in 12/66522 (0.018%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). The A87P variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A87P as a likely pathogenic variant.
Invitae RCV000006357 SCV000766638 likely pathogenic Griscelli syndrome type 2 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 87 of the RAB27A protein (p.Ala87Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs104894497, ExAC 0.02%). This variant has been reported in combination with other pathogenic RAB27A variants in two individuals affected with familial hemophagocytic lymphohistiocytosis or Griscelli syndrome type 2 (PMID: 16278825, 25544030). ClinVar contains an entry for this variant (Variation ID: 5991). Experimental studies have shown that this missense change impairs the function of the encoded protein by impairing the interaction with its protein partner and causing delayed responses at the immunologic synapse (PMID: 26880764, 16278825). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.
OMIM RCV000006357 SCV000026539 pathogenic Griscelli syndrome type 2 2006-01-01 no assertion criteria provided literature only

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