rs61748449

Positions:

• chr19-47839593-CG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000554.6(CRX):​c.529del​(p.Ala177LeufsTer10) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRX NM_000554.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:2
• Conservation: PhyloP100: 1.86

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 Likely_pathogenic. Variant got 6 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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRX	NM_000554.6	c.529del	p.Ala177LeufsTer10	frameshift_variant	4/4	ENST00000221996.12	NP_000545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRX	ENST00000221996.12	c.529del	p.Ala177LeufsTer10	frameshift_variant	4/4	2	NM_000554.6	ENSP00000221996	P1
CRX	ENST00000613299.1	c.*251del		3_prime_UTR_variant	3/3	3		ENSP00000478106

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 03, 2022

This sequence change creates a premature translational stop signal (p.Ala177Leufs*10) in the CRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 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 autosomal dominant retinitis pigmentosa (PMID: 11910559). This variant is also known as A177delta1bp. ClinVar contains an entry for this variant (Variation ID: 65614). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Leber congenital amaurosis 7 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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: rs61748449; hg19: chr19-48342850;