Submissions for variant NM_014249.4(NR2E3):c.230G>A (p.Arg77Gln)

gnomAD frequency: 0.00087  dbSNP: rs186714117

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000487685	SCV000340409	uncertain significance	not provided	2016-04-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487685	SCV000575011	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000487685	SCV000618630	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The R77Q variant in the NR2E3 gene has been reported previously in an unaffected control, but not in an affected individual, to our knowledge (Kanda et al., 2009). The R77Q variant is observed in 74/32,990 (0.22%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R77Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R77Q as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000487685	SCV001219114	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 77 of the NR2E3 protein (p.Arg77Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs186714117, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NR2E3-related conditions. ClinVar contains an entry for this variant (Variation ID: 286837). 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. 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.
Illumina Laboratory Services, Illumina	RCV001119726	SCV001278157	uncertain significance	Enhanced S-cone syndrome	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001119727	SCV001278158	uncertain significance	Retinitis pigmentosa 37	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001119727	SCV002505541	uncertain significance	Retinitis pigmentosa 37	2022-04-25	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_014249.4:c.311G>A._x000D_ Criteria applied: PM3_STR, PM2_SUP
Natera, Inc.	RCV001275372	SCV001460502	uncertain significance	Goldmann-Favre syndrome	2020-09-16	no assertion criteria provided	clinical testing