rs864309708

chr19-47839727-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000554.6(CRX):c.661del(p.Tyr221ThrfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRX NM_000554.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-47839727-CT-C is Pathogenic according to our data. Variant chr19-47839727-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 218923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-47839727-CT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6	c.661del	p.Tyr221ThrfsTer9	frameshift_variant	4/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRX	ENST00000221996.12	c.661del	p.Tyr221ThrfsTer9	frameshift_variant	4/4	2	NM_000554.6	P1
CRX	ENST00000613299.1	c.*383del		3_prime_UTR_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

This sequence change creates a premature translational stop signal (p.Tyr221Thrfs*9) in the CRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the CRX protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with bull's eye maculopathy (PMID: 25259927). ClinVar contains an entry for this variant (Variation ID: 218923). This variant disrupts a region of the CRX protein in which other variant(s) (p.Tyr258*) have been determined to be pathogenic (PMID: 22968130, 25270190). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Benign concentric annular macular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 25, 2014

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Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs864309708; hg19: chr19-48342984;