Submissions for variant NM_020366.4(RPGRIP1):c.3793_3794insGAAA (p.Val1265fs)

gnomAD frequency: 0.00001  dbSNP: rs1468976582

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001005015	SCV001164577	uncertain significance	Leber congenital amaurosis 6	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Val1265GlyfsTer19 variant in RPGRIP1 was identified by our study in the compound heterozygous state with an exon duplication in the same gene in one individual with Leber congenital amaurosis (PMID: 30072743). The presence of this variant in combination with an exon duplication variant and in an individual with Leber congenital amaurosis increases the likelihood that the p.Val1265GlyfsTer19 variant is pathogenic. The p.Val1265GlyfsTer19 variant in RPGRIP1 has not been previously reported in individuals with Leber congenital amaurosis but has been identified in 0.0009014% (1/110936) of European (non-Finnish) chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1265 and leads to a premature termination codon 19 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Greater than 10% of pathogenic variants reported in association with Leber Congenital Amaurosis in ClinVar are loss of function variants, including at least three pathogenic loss of function variants across multiple exons. Loss of function of the RPGRIP1 gene is an established disease mechanism in autosomal recessive Leber Congenital Amarosis. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM3_Supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860574	SCV002178552	uncertain significance	Cone-rod dystrophy 13; Leber congenital amaurosis 6	2020-12-20	criteria provided, single submitter	clinical testing	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. This variant has been observed in individual(s) with clinical features of Leber congenital amaurosis (PMID: 25412400, 30072743). ClinVar contains an entry for this variant (Variation ID: 814009). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val1265Glyfs*19) in the RPGRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the RPGRIP1 protein.