ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Cys219Valfs*4) in the NRL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the NRL protein. This variant is present in population databases (rs761024023, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clumped pigmentary retinal degeneration and/or retinitis pigmentosa (PMID: 29385733, 36819107). ClinVar contains an entry for this variant (Variation ID: 853152). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NRL function (PMID: 17335001). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

The p.Cys219ValfsX4 variant in NRL has been reported in two individuals with retinal disease including one heterozygote and one compound heterozygote and segregated with disease in one affected individual (Nishiguchi 2004 PMID: 15591106, Neveling 2012 PMID: 22334370, Littink 2018 PMID: 29385733). It has also been identified in 0.049% (10/20032) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 853152). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 219 and leads to a premature termination codon four amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that this variant impacts protein function (Kanda 2007 PMID: 17335001); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PVS1_Moderate, PS3_Supporting, PP1

The NRL c.654delC variant is predicted to result in a frameshift and premature protein termination (p.Cys219Valfs*4). This variant has been reported in individuals with autosomal recessive retinal disease (Neveling et al. 2012. PubMed ID: 22334370; Littink et al. 2018. PubMed ID: 29385733; Panneman et al. 2023. PubMed ID: 36819107). This variant is reported in 0.050% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in NRL are expected to be pathogenic for autosomal recessive disease. This variant is interpreted as likely pathogenic.