ClinVar Genomic variation as it relates to human health

Variant summary: NR2E3 c.226C>T (p.Arg76Trp) results in a non-conservative amino acid change located in the Zinc finger, nuclear hormone receptor-type domain (IPR001628) / DNA-binding domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 229784 control chromosomes. c.226C>T has been reported in the literature in compound heterozygous individuals affected with retinitis pigmentosa, enhanced rod cone syndrome, or retinal dystrophy in settings of multi-gene panel testing (examples: Ge_2015, Stone_2017, Zampaglione_2020, Al-khuzaei_2020) or in individuals affected with enhanced rod cone syndrome without a second reported variant (example: Haider_2000). These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function, with the most pronounced variant effect showing a complete loss of DNA binding ability (examples: Roduit_2009, Kanda_2009, Barrera_2016). The following publications have been ascertained in the context of this evaluation (PMID: 33138239, 27013732, 26667666, 10655056, 19898638, 15689355, 19823680, 28559085, 32037395). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate a damaging effect; reduces activation of the target promoter, rhodopsin (Roduit et al., 2009; Kanda A and Swaroop, 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A different missense change at this residue (R76Q) has been reported as likely pathogenic at GeneDx and in the published literature in association with NR2E3-related retinal dystrophies (Li et al., 2017; Murro et al., 2019); This variant is associated with the following publications: (PMID: 27013732, 19898638, 10655056, 15689355, 16225923, 28559085, 17564971, 33138239, 32037395, 26667666, 19718767, 19823680)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 76 of the NR2E3 protein (p.Arg76Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with enhanced S cone syndrome or autosomal recessive retinitis pigmentosa (PMID: 10655056, 26667666, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NR2E3 protein function. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19823680, 19898638, 27013732). This variant disrupts the p.Arg76 amino acid residue in NR2E3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19823680, 19898638, 27013732, 28418496, 30324420; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The NR2E3 c.226C>T variant is predicted to result in the amino acid substitution p.Arg76Trp. This variant has been reported in the compound heterozygous state in individuals with enhanced S-cone syndrome and related retinal disease (Haider et al. 2000. PubMed ID: 10655056; Ge et al. 2015. PubMed ID: 26667666; Table S1, Stone et al. 2017. PubMed ID: 28559085; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD. Given the evidence. we interpret this variant as pathogenic for autosomal recessive disease.