Submissions for variant NM_183235.3(RAB27A):c.418C>G (p.Gln140Glu)

gnomAD frequency: 0.00031  dbSNP: rs150463407

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644919	SCV000766641	likely benign	Griscelli syndrome type 2	2024-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000644919	SCV001274477	uncertain significance	Griscelli syndrome type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263883	SCV002542927	uncertain significance	Autoinflammatory syndrome	2020-03-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354874	SCV001549591	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RAB27A p.Gln140Glu variant was not identified in the literature but was identified in dbSNP (ID: rs150463407) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 101 of 282708 chromosomes at a frequency of 0.0003573 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 83 of 129094 chromosomes (freq: 0.000643), Ashkenazi Jewish in 4 of 10366 chromosomes (freq: 0.000386), Other in 2 of 7218 chromosomes (freq: 0.000277), Latino in 9 of 35438 chromosomes (freq: 0.000254) and African in 3 of 24962 chromosomes (freq: 0.00012), but was not observed in the East Asian, European (Finnish), or South Asian populations. The p.Gln140 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.