Submissions for variant NM_183235.3(RAB27A):c.550C>T (p.Arg184Ter)

gnomAD frequency: 0.00006  dbSNP: rs200956636

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000499859	SCV000596645	pathogenic	Griscelli syndrome type 2	2016-06-27	criteria provided, single submitter	clinical testing
Invitae	RCV000499859	SCV000819625	pathogenic	Griscelli syndrome type 2	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg184*) in the RAB27A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the RAB27A protein. This variant is present in population databases (rs200956636, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Griscelli syndrome (PMID: 10835631, 15475639, 18397837, 19030707, 19953648, 25071262, 25500851). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 436458). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001090829	SCV001246576	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263709	SCV002542931	pathogenic	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000499859	SCV004047341	pathogenic	Griscelli syndrome type 2		criteria provided, single submitter	clinical testing	This stop gained variant c.550C>T (p.Arg184Ter) has been reported in homozygous or in compound heterozygous state in individuals and families affected with Griscelli syndrome (Ariffin H et al), and has been shown to segregate with disease in two families (Meeths M et al). The c.550C>T variant is reported with the allele frequency of 0.006364% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This sequence change results in a premature translational stop signal in the RAB27A gene (p.Arg184*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acids of the RAB27A protein. The nucleotide change c.550C>T in RAB27A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000499859	SCV004244275	pathogenic	Griscelli syndrome type 2		criteria provided, single submitter	clinical testing
OMIM	RCV000499859	SCV000026532	pathogenic	Griscelli syndrome type 2	2000-06-01	no assertion criteria provided	literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000499859	SCV000804202	likely pathogenic	Griscelli syndrome type 2	2018-08-25	no assertion criteria provided	clinical testing	The observed variant c.550C>T (p.Arg184Ter) has not been reported in 1000 Genomes database and has a minor allele frequency of 0.007% in the ExAC database. The in silico prediction of the given variant is damaging by MutationTaster2 and LRT.