Submissions for variant NM_006269.2(RP1):c.5797C>T (p.Arg1933Ter)

gnomAD frequency: 0.00008  dbSNP: rs118031911

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825444	SCV000966744	uncertain significance	not specified	2018-12-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1933X variant in RP1 has been reported in the heterozygous state in 4 individuals with occult macular dystrophy, in 1 homozygous individual with retinitis pigmentosa, and in 4 individuals with hereditary ciliary retinopathy in compound heterozygo sity with an Alu insertion (c.4052_4053ins328) (Fujinami 2016, Li 2018, Maeda 20 18, Nikopoulos 2018). It has also been identified in 0.2% (41/19950) of East Asi an chromosomes by gnomAD (http://gnomad.broadinstitute.org).This nonsense varian t leads to a premature termination codon at position 1933. This alteration occur s within the last exon and is, therefore, likely to escape nonsense mediated dec ay (NMD) and result in a truncated protein. In summary, while there is some susp icion for a pathogenic role, the clinical significance of the p.Arg1933X variant is uncertain. ACMG/AMP Criteria applied: PM4, PM3.
Invitae	RCV001035254	SCV001198577	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431, 33681214). Therefore, variants that disrupt this region are expected to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 143136). This premature translational stop signal has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 31253780). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 29425069, 30913292, 31253780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs118031911, gnomAD 0.2%). This sequence change creates a premature translational stop signal (p.Arg1933*) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 224 amino acid(s) of the RP1 protein.
Illumina Laboratory Services, Illumina	RCV000132661	SCV001325378	benign	Retinitis pigmentosa	2017-05-04	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
GeneDx	RCV001035254	SCV001830662	likely pathogenic	not provided	2020-11-30	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 224 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 33090715, 31980526, 15183808, 31054281, 30913292, 11857735, 16085945, 29785639, 31253780, 12048676, 12901510, 22321012, 18450588, 15994872, 11694261, 11317367, 27623337, 29425069)
3billion	RCV002250573	SCV002521245	pathogenic	Retinitis pigmentosa 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.017%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000143136 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Dept Of Ophthalmology, Nagoya University	RCV003888563	SCV004706761	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132661	SCV000172612	probable-pathogenic	Retinitis pigmentosa		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.