Submissions for variant NM_014249.4(NR2E3):c.931C>T (p.Arg311Trp)

gnomAD frequency: 0.00001  dbSNP: rs767442358

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485007	SCV000571451	likely pathogenic	not provided	2016-08-23	criteria provided, single submitter	clinical testing	The R311W variant in the NR2E3 gene has been reported previously, in cis with another NR2E3 missense variant, in one individual with a suspected NR2E3-related retinal disorder; however, additional information regarding familial segregation, specific clinical phenotype, and the presence or absence of another variant on the second NR2E3 allele was not provided (Coppieters et al., 2009). This variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species, the R311W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same amino acid residue (R311Q) has been previously reported in association with enhanced S-cone syndrome (Haider et al., 2000; Milam et al., 2002; Escher et al., 2009), supporting the functional importance of this region of the protein. The R311W variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485007	SCV001564334	uncertain significance	not provided	2024-05-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 311 of the NR2E3 protein (p.Arg311Trp). This variant is present in population databases (rs767442358, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of autosomal recessive enhanced S-cone syndrome, retinal dystrophy, and/or retinitis pigmentosa (PMID: 30054919, 32531858, 36819107). ClinVar contains an entry for this variant (Variation ID: 422071). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NR2E3 protein function. This variant disrupts the p.Arg311 amino acid residue in NR2E3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11071390, 16024868). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000485007	SCV003917407	likely pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	NR2E3: PM2, PM3, PM5, PP4, BP4
Baylor Genetics	RCV003470575	SCV004191607	likely pathogenic	Enhanced S-cone syndrome	2024-03-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816695	SCV005071012	likely pathogenic	Retinal dystrophy	2019-01-01	criteria provided, single submitter	clinical testing