Submissions for variant NM_015272.5(RPGRIP1L):c.1061A>G (p.Glu354Gly)

gnomAD frequency: 0.00004  dbSNP: rs752128105

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519061	SCV000618835	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RPGRIP1L gene. The E354G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E354G 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 E354G 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 Human Gene Mutation Database in association with RPGRIP1L-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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001338566	SCV001532246	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with glycine at codon 354 of the RPGRIP1L protein (p.Glu354Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs752128105, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 450277). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002481707	SCV002776304	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2022-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829490	SCV002085745	uncertain significance	Familial aplasia of the vermis	2020-03-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527631	SCV004106147	uncertain significance	RPGRIP1L-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The RPGRIP1L c.1061A>G variant is predicted to result in the amino acid substitution p.Glu354Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0081% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.