Submissions for variant NM_012233.3(RAB3GAP1):c.748+1G>A

dbSNP: rs587776651

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578621	SCV000680759	pathogenic	not provided	2017-11-28	criteria provided, single submitter	clinical testing	The c.748+1G>A variant in the RAB3GAP1 gene has been reported previously in association with Warburg Micro syndrome, and is considered a founder mutation in the Turkish population (Handley et al., 2013). This splice site variant destroys the canonical splice donor site of intron 8. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.748+1G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.748+1G>A as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578621	SCV000932155	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the RAB3GAP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAB3GAP1 are known to be pathogenic (PMID: 23420520). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Warburg Micro syndrome (PMID: 15696165, 23420520, 26852512). ClinVar contains an entry for this variant (Variation ID: 7058). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000007474	SCV002574809	pathogenic	Warburg micro syndrome 1	2022-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512875	SCV003620053	pathogenic	Inborn genetic diseases	2022-06-17	criteria provided, single submitter	clinical testing	The c.748+1G>A intronic variant results from a G to A substitution one nucleotide(s) after coding exon 8 of the RAB3GAP1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in the homozygous state is several Turkish individuals with Warburg micro syndrome (Aligianis, 2005; Morris-Rosendahl, 2010; Handley, 2012; Handley, 2013; Tasdemir, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000007474	SCV003922350	pathogenic	Warburg micro syndrome 1	2023-05-02	criteria provided, single submitter	curation	The homozygous c.748+1G>A variant in RAB3GAP1 was identified by our study in one individual with congenital cataracts, corpus callosum atrophy, spastic tetraparesis, and neurodevelopmental delay. The c.748+1G>A variant in RAB3GAP1 has been previously reported in 10 individuals with Warburg micro syndrome 1 (PMID: 31319225, PMID: 23420520, PMID: 26852512, PMID: 17351351, PMID: 15696165), but has been identified in 0.0008% (1/125568) of chromosomes by TopMed Bravo (https://bravo.sph.umich.edu/, dbSNP ID: rs587776651). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 7058) and has been interpreted as pathogenic by GeneDx, Erasmus Medical Center, Invitae, Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, and OMIM. The 10 affected individuals previously reported were homozygotes (PMID: 31319225, PMID: 23420520, PMID: 26852512, PMID: 17351351, PMID: 15696165), which increases the likelihood that the c.748+1G>A variant is pathogenic. This variant is located in the 5’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. Loss of function of the RAB3GAP1 gene is an established disease mechanism in autosomal recessive Warburg micro syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Warburg micro syndrome 1. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).
OMIM	RCV000007474	SCV000027674	pathogenic	Warburg micro syndrome 1	2013-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000007474	SCV000778354	not provided	Warburg micro syndrome 1		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000578621	SCV001953631	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000578621	SCV001975369	pathogenic	not provided		no assertion criteria provided	clinical testing