ClinVar Miner

Submissions for variant NM_183235.3(RAB27A):c.467+1G>C

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000705980 SCV000835006 likely pathogenic Griscelli syndrome type 2 2018-03-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 5) of the RAB27A gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs756071120, ExAC 0.009%). This variant has been reported as homozygous in several individuals affected with Griscelli syndrome or haemophagocytic lymphohistiocytosis (PMID: 10835631, 23160464), and has been observed on the opposite chromosome (in trans) from a c.352C>T (p.Glu118*) variant in an individual affected with Griscelli syndrome (PMID: 15163896). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that the patient lymphocytes carrying the compound heterozygous RAB27A changes c.467+1G>C and c.352C>T (p.Glu118*) exhibit elevated proliferation rate, increased HLA-DR expression, and impaired NK and T cell cytotoxic activities that could be restored by transfected RAB27A cDNA (PMID: 15163896). 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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