ClinVar Miner

Submissions for variant NM_006269.2(RP1):c.5797C>T (p.Arg1933Ter) (rs118031911)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 likely pathogenic not provided 2020-07-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RP1 gene (p.Arg1933*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 224 amino acids of the RP1 protein. This variant is present in population databases (rs118031911, ExAC 0.2%) and has an allele count higher than expected for a pathogenic variant (PMID: 31253780). It has been observed to be homozygous in several individuals who were not affected with retinal disease (PMID: 31253780). This variant has been observed to segregate with autosomal recessive retinal disease in several families (PMID: 30913292, 31253780). In several affected individuals the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (PMID: 29425069, 30913292, 31253780). ClinVar contains an entry for this variant (Variation ID: 143136). In summary, the currently available evidence indicates that the variant is pathogenic, but because it has a high allele frequency and is found in homozygosity in unaffected individuals, additional evidence is required to prove its pathogenicity conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Clinical Services Laboratory,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.
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.

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