Submissions for variant NM_012233.3(RAB3GAP1):c.2839C>T (p.Arg947Cys)

gnomAD frequency: 0.00006  dbSNP: rs751620093

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500116	SCV000596654	uncertain significance	not specified	2015-12-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000766903	SCV000619107	uncertain significance	not provided	2017-07-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RAB3GAP1 gene. The R947C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R947C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R947C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with association with RAB3GAP1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV001132508	SCV001292169	uncertain significance	Warburg micro syndrome 1	2018-01-17	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.
Ambry Genetics	RCV003243158	SCV003942230	uncertain significance	Inborn genetic diseases	2023-04-05	criteria provided, single submitter	clinical testing	The c.2839C>T (p.R947C) alteration is located in exon 24 (coding exon 24) of the RAB3GAP1 gene. This alteration results from a C to T substitution at nucleotide position 2839, causing the arginine (R) at amino acid position 947 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.