Submissions for variant NM_004698.4(PRPF3):c.1481C>T (p.Thr494Met)

dbSNP: rs121434241

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726757	SCV000702812	pathogenic	not provided	2016-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000726757	SCV001206884	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 494 of the PRPF3 protein (p.Thr494Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 11773002, 15085354, 20309403, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3352). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRPF3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PRPF3 function (PMID: 17932117, 20811066). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074785	SCV001240381	pathogenic	Retinal dystrophy	2019-06-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726757	SCV001245935	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074785	SCV005070316	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV000003516	SCV005881533	pathogenic	Retinitis pigmentosa 18	2025-02-05	criteria provided, single submitter	clinical testing	Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Other variants at this amino acid residue have been classified as pathogenic/likely pathogenic (PM5, p.Arg218Leu; p.Arg218Gly; p,Arg218Cys. REVEL score is 0.923 (PP3_mod). Prevalence in affected patients is greater compared to the general populace (PS4). Experimental studies have shown that this missense change affects PRPF3 function (PS3, PMID: 17932117;20811066)
GeneDx	RCV000726757	SCV005881988	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Identified in individuals with retinitis pigmentosa and segregates with disease in several families in published literature (PMID: 11773002, 32037395, 23049240, 28848678); Published functional studies demonstrate a damaging effect (PMID: 20811066, 17932117, 25111227); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32531858, 35138024, 15085354, 29847639, 28559085, 31054281, 31456290, 31816670, 36460718, 33749171, 25111227, 27886254, 11971898, 21283520, 21378395, 11773002, 20811066, 20309403, 17932117, 23049240, 33623043, 30628748, 23647439, 16799052, 28350375, 34662339, 31726916, 27302685, 28848678, 32037395)
OMIM	RCV000003516	SCV000023674	pathogenic	Retinitis pigmentosa 18	2008-01-15	no assertion criteria provided	literature only
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003129	SCV001161198	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Department of Genetics, Fundacion Jimenez Diaz University Hospital	RCV001003129	SCV001450576	uncertain significance	Retinitis pigmentosa		flagged submission	clinical testing	Variant not found in population databases, predicted deleterious by in-silico pathogenicity predictors, and previously reported in literature (PMID: 27898983). (ACMG: PM2 Moderate, PP3 Supporting; PP5 Supporting)