Submissions for variant NM_014249.4(NR2E3):c.767C>T (p.Ala256Val)

dbSNP: rs377257254

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046776	SCV001210691	likely pathogenic	not provided	2024-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 256 of the NR2E3 protein (p.Ala256Val). This variant is present in population databases (rs377257254, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive enhanced S-cone syndrome (PMID: 17601449, 25703721). 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: 844032). 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 not expected to disrupt NR2E3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect NR2E3 function (PMID: 25703721). This variant disrupts the p.Ala256 amino acid residue in NR2E3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12963616, 19898638, 25079116). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV001118395	SCV001276669	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	RCV001119921	SCV001278373	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV001118395	SCV004191611	likely pathogenic	Enhanced S-cone syndrome	2024-03-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004813600	SCV005068876	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001118395	SCV002085619	uncertain significance	Enhanced S-cone syndrome	2020-08-17	no assertion criteria provided	clinical testing