Submissions for variant NM_020366.4(RPGRIP1):c.2435G>A (p.Arg812Gln)

gnomAD frequency: 0.00024  dbSNP: rs190490019

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001089439	SCV001020850	benign	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2024-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000878013	SCV001149117	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110510	SCV001267959	uncertain significance	Cone-rod dystrophy 13	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001110511	SCV001267960	uncertain significance	Leber congenital amaurosis 6	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001110511	SCV002046023	likely benign	Leber congenital amaurosis 6	2021-11-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001110510	SCV002046034	likely benign	Cone-rod dystrophy 13	2021-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930456	SCV004742440	likely benign	RPGRIP1-related disorder	2020-05-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001110511	SCV001553339	likely benign	Leber congenital amaurosis 6		no assertion criteria provided	clinical testing	The RPGRIP1 p.R812Q variant was identified in two heterozygous probands with Leber congenital amaurosis, as well as one unaffected father (Henderson_2007_PMID: 18055820; Vallespin_2007_PMID: 18055816). The variant was identified in dbSNP (ID: rs190490019) and ClinVar (classified as benign by Invitae and as uncertain significance by Illumina and CeGaT Praxis). The variant was identified in control databases in 269 of 280214 chromosomes (4 homozygous) at a frequency of 0.0009600, and was observed at the highest frequency in the South Asian population in 192 of 30602 chromosomes (4 homozygous) (freq: 0.006274) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R812 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.