rs104894673

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_000554.6(CRX):c.268C>T(p.Arg90Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,332 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. R90Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CRX
NM_000554.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1O:1

Conservation

PhyloP100: 4.26

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000554.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 19-47839335-C-T is Pathogenic according to our data. Variant chr19-47839335-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7422.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, not_provided=1, Uncertain_significance=1}. Variant chr19-47839335-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-47839335-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6 linkuse as main transcript	c.268C>T	p.Arg90Trp	missense_variant	4/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRX	ENST00000221996.12 linkuse as main transcript	c.268C>T	p.Arg90Trp	missense_variant	4/4	2	NM_000554.6	P1
CRX	ENST00000613299.1 linkuse as main transcript	c.116C>T	p.Pro39Leu	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461288

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000575

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leber congenital amaurosis 7

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital	Aug 20, 2021	- -

Retinal dystrophy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 06, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

not provided

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2022	Observed in homozygous state in a patient with Leber congenital amaurosis in the literature (Swaroop et al., 1999) and not observed in homozygous state in controls; Published functional studies demonstrate a significant reduction in protein function with loss of DNA binding affinity and change in specificity (Swaroop et al., 1999; Barrera et al., 2016); 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: 34426522, 24516401, 27013732, 11971869, 10887186, 9931337, 22113834, 31626798, 31054281, 32533067, 32689858) -
not provided, no classification provided	literature only	Retina International	-	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the CRX protein (p.Arg90Trp). This variant is present in population databases (rs104894673, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of CRX-related conditions (PMID: 9931337, 32533067, 32689858; Invitae). ClinVar contains an entry for this variant (Variation ID: 7422). 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 CRX protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CRX function (PMID: 9931337, 11971869, 24516401). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.54

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.84

MutationTaster

Benign

1.0

A;A;A

Vest4

0.49

MVP

0.93

ClinPred

1.0

GERP RS

3.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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