19-47836263-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000554.6(CRX):c.121C>T(p.Arg41Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,874 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. R41P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

CRX (HGNC:2383): (cone-rod homeobox) The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

CRX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity CRX_HUMAN there are 29 pathogenic changes around while only 2 benign (94%) in NM_000554.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-47836264-G-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 19-47836263-C-T is Pathogenic according to our data. Variant chr19-47836263-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-47836263-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-47836263-C-T is described in Lovd as [Pathogenic]. Variant chr19-47836263-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRX	NM_000554.6 link	c.121C>T	p.Arg41Trp	missense_variant	Exon 3 of 4	ENST00000221996.12	NP_000545.1	O43186

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRX	ENST00000221996.12 link	c.121C>T	p.Arg41Trp	missense_variant	Exon 3 of 4	2	NM_000554.6	ENSP00000221996.5	O43186
CRX	ENST00000556527.1 link	n.98C>T		non_coding_transcript_exon_variant	Exon 2 of 2	1
CRX	ENST00000566686.5 link	c.121C>T	p.Arg41Trp	missense_variant	Exon 3 of 3	5		ENSP00000457808.2	H3BUU7
CRX	ENST00000613299.1 link	c.100+1720C>T		intron_variant	Intron 2 of 2	3		ENSP00000478106.1	A0A087WTS9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251204

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cone-rod dystrophy 2

Pathogenic:5

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:9427255). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007418). A different missense change at the same codon (p.Arg41Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007421). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Other variants at this amino acid residue have been classified as pathogenic/likely pathogenic (PM5, p.Arg41Pro; p.Arg41Gln). REVEL score is 0.954 (PP3_str). Prevalence of variant is significantly increased in affected patient compared to the general population (PS4). Cosegregation with disease observed in multiple families in multiple studies (PP1, PMID:9427255 + internal data) -

not provided

Pathogenic:3Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect; functional assays demonstrate decreased DNA binding activity and reduced trans-activation activity (PMID: 11971869, PMID: 9427255, PMID: 10887186); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 26992781, 26957898, 33629268, 34758253, 36536961, 36460718, 31213501, 36819107, 36909829, 33749171, 36284460, 9427255, 12819982, 27013732, 20513135, 10967037, 10887186, 31203166, 30910914, 33836713, 32533067, 35119454, 11971869) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:3

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 01, 2016

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy

Pathogenic:1

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2

Pathogenic:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 41 of the CRX protein (p.Arg41Trp). This variant is present in population databases (rs104894672, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal dominant CRX-related conditions (PMID: 9427255). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CRX protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CRX function (PMID: 9427255). This variant disrupts the p.Arg41 amino acid residue in CRX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9427255, 10916183, 11748859, 24265693, 30543658). 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. -

Retinitis pigmentosa

Pathogenic:1

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

.;H;H

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.013

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.94, 0.95

MutPred

0.94

Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);Loss of disorder (P = 0.0088);

MVP

0.98

MPC

0.74

ClinPred

1.0

GERP RS

3.7

Varity_R

0.87

gMVP

0.86

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