rs527236086
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5
The NM_014249.4(NR2E3):c.364C>T(p.Arg122Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,550,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122H) has been classified as Uncertain significance.
Frequency
Consequence
NM_014249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR2E3 | NM_014249.4 | c.364C>T | p.Arg122Cys | missense_variant | 4/8 | ENST00000617575.5 | |
NR2E3 | NM_016346.4 | c.364C>T | p.Arg122Cys | missense_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR2E3 | ENST00000617575.5 | c.364C>T | p.Arg122Cys | missense_variant | 4/8 | 1 | NM_014249.4 | P1 | |
NR2E3 | ENST00000621098.1 | c.364C>T | p.Arg122Cys | missense_variant | 4/7 | 1 | |||
NR2E3 | ENST00000621736.4 | c.100C>T | p.Arg34Cys | missense_variant | 6/10 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000260 AC: 4AN: 153982Hom.: 0 AF XY: 0.0000366 AC XY: 3AN XY: 81994
GnomAD4 exome AF: 0.0000229 AC: 32AN: 1398730Hom.: 0 Cov.: 33 AF XY: 0.0000217 AC XY: 15AN XY: 690020
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Enhanced S-cone syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 14, 2023 | - - |
NR2E3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2024 | The NR2E3 c.364C>T variant is predicted to result in the amino acid substitution p.Arg122Cys. This variant has been reported in the homozygous state in two siblings with retinitis pigmentosa from a consanguineous family (Family RP670, Bocquet et al. 2013. PubMed ID: 24339724). This variant has also been reported in the homozygous and compound heterozygous states in additional unrelated individuals with retinal dystrophies (Murro et al. 2018. PubMed ID: 30324420; Patient K6189, Table S6, Oishi et al. 2014. PubMed ID: 25324289; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395). This variant is reported in 0.0081% of alleles in individuals of East Asian descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the NR2E3 protein (p.Arg122Cys). 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 clinical features of autosomal recessive NR2E3-related conditions (PMID: 24339724, 30324420, 32037395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143147). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 19, 2019 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Department of Ophthalmology and Visual Sciences Kyoto University | - | - - |
Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at