15-71811590-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_014249.4(NR2E3):c.226C>T(p.Arg76Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,603,804 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -0.526

Variant links:

Genes affected

NR2E3 (HGNC:7974): (nuclear receptor subfamily 2 group E member 3) This protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as in maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding. This gene encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. Defects in this gene are a cause of enhanced S cone syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

NR2E3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_014249.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-71811591-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5530.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Likely_pathogenic=2, Uncertain_significance=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

PP5

Variant 15-71811590-C-T is Pathogenic according to our data. Variant chr15-71811590-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811590-C-T is described in Lovd as [Pathogenic]. Variant chr15-71811590-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2E3	NM_014249.4 linkuse as main transcript	c.226C>T	p.Arg76Trp	missense_variant	2/8	ENST00000617575.5
NR2E3	NM_016346.4 linkuse as main transcript	c.226C>T	p.Arg76Trp	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2E3	ENST00000617575.5 linkuse as main transcript	c.226C>T	p.Arg76Trp	missense_variant	2/8	1	NM_014249.4	P1	Q9Y5X4-1
NR2E3	ENST00000621098.1 linkuse as main transcript	c.226C>T	p.Arg76Trp	missense_variant	2/7	1			Q9Y5X4-2
NR2E3	ENST00000621736.4 linkuse as main transcript	c.-39C>T		5_prime_UTR_variant	4/10	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000305

AC:

AN:

229784

Hom.:

AF XY:

0.0000401

AC XY:

AN XY:

124782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000309

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000143

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1451636

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

721098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Enhanced S-cone syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 28, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2000	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 76 of the NR2E3 protein (p.Arg76Trp). 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 enhanced S cone syndrome or autosomal recessive retinitis pigmentosa (PMID: 10655056, 26667666, 28559085). 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: 5529). 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. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19823680, 19898638, 27013732). This variant disrupts the p.Arg76 amino acid residue in NR2E3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19823680, 19898638, 27013732, 28418496, 30324420; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2022	Published functional studies demonstrate a damaging effect; reduces activation of the target promoter, rhodopsin (Roduit et al., 2009; Kanda A and Swaroop, 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A different missense change at this residue (R76Q) has been reported as likely pathogenic at GeneDx and in the published literature in association with NR2E3-related retinal dystrophies (Li et al., 2017; Murro et al., 2019); This variant is associated with the following publications: (PMID: 27013732, 19898638, 10655056, 15689355, 16225923, 28559085, 17564971, 33138239, 32037395, 26667666, 19718767, 19823680) -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 11, 2023

Variant summary: NR2E3 c.226C>T (p.Arg76Trp) results in a non-conservative amino acid change located in the Zinc finger, nuclear hormone receptor-type domain (IPR001628) / DNA-binding domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 229784 control chromosomes. c.226C>T has been reported in the literature in compound heterozygous individuals affected with retinitis pigmentosa, enhanced rod cone syndrome, or retinal dystrophy in settings of multi-gene panel testing (examples: Ge_2015, Stone_2017, Zampaglione_2020, Al-khuzaei_2020) or in individuals affected with enhanced rod cone syndrome without a second reported variant (example: Haider_2000). These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function, with the most pronounced variant effect showing a complete loss of DNA binding ability (examples: Roduit_2009, Kanda_2009, Barrera_2016). The following publications have been ascertained in the context of this evaluation (PMID: 33138239, 27013732, 26667666, 10655056, 19898638, 15689355, 19823680, 28559085, 32037395). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

-0.070

Cadd

Benign

Dann

Benign

0.91

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.15

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Pathogenic

0.81

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.85

Loss of disorder (P = 0.0967);Loss of disorder (P = 0.0967);

MVP

0.72

ClinPred

0.66

GERP RS

1.7

Varity_R

0.37

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over