Submissions for variant NM_020366.4(RPGRIP1):c.2663G>A (p.Arg888Gln)

gnomAD frequency: 0.00004  dbSNP: rs559905596

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001113275	SCV001271037	uncertain significance	Leber congenital amaurosis 6	2018-01-13	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.
Illumina Laboratory Services, Illumina	RCV001113276	SCV001271038	uncertain significance	Cone-rod dystrophy 13	2018-01-13	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.
Invitae	RCV001316219	SCV001506826	uncertain significance	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 888 of the RPGRIP1 protein (p.Arg888Gln). This variant is present in population databases (rs559905596, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RPGRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 883114). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Genome-Nilou Lab	RCV001113275	SCV002045122	uncertain significance	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001113276	SCV002045133	uncertain significance	Cone-rod dystrophy 13	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002556209	SCV003760557	uncertain significance	Inborn genetic diseases	2022-02-11	criteria provided, single submitter	clinical testing	The c.2663G>A (p.R888Q) alteration is located in exon 16 (coding exon 16) of the RPGRIP1 gene. This alteration results from a G to A substitution at nucleotide position 2663, causing the arginine (R) at amino acid position 888 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.