rs397515360

Positions:

• chr8-86643780-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_019098.5(CNGB3):​c.1148del​(p.Thr383IlefsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00227 in 1,606,146 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: CNGB3 NM_019098.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:45 O:1
• Conservation: PhyloP100: 6.13

Genes affected

CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-86643780-AG-A is Pathogenic according to our data. Variant chr8-86643780-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-86643780-AG-A is described in Lovd as [Pathogenic]. Variant chr8-86643780-AG-A is described in Lovd as [Pathogenic]. Variant chr8-86643780-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr8-86643780-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNGB3	NM_019098.5	c.1148del	p.Thr383IlefsTer13	frameshift_variant	10/18	ENST00000320005.6	NP_061971.3
CNGB3	XM_011517138.3	c.734del	p.Thr245IlefsTer13	frameshift_variant	8/16		XP_011515440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNGB3	ENST00000320005.6	c.1148del	p.Thr383IlefsTer13	frameshift_variant	10/18	1	NM_019098.5	ENSP00000316605	P1
CNGB3	ENST00000681546.1	n.968del		non_coding_transcript_exon_variant	5/13
CNGB3	ENST00000681746.1	c.1148del	p.Thr383IlefsTer13	frameshift_variant, NMD_transcript_variant	10/19			ENSP00000505959

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 267 AN: 148896 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000542

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00271

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00311

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.00172 AC: 431 AN: 250592 Hom.: 2 AF XY: 0.00167 AC XY: 226 AN XY: 135456

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00232 AC: 3384 AN: 1457132 Hom.: 7 Cov.: 31 AF XY: 0.00221 AC XY: 1601 AN XY: 724992

Gnomad4 AFR exome AF: 0.000481

Gnomad4 AMR exome AF: 0.000763

Gnomad4 ASJ exome AF: 0.000347

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.00289

Gnomad4 NFE exome AF: 0.00271

Gnomad4 OTH exome AF: 0.00213

GnomAD4 genome AF: 0.00179 AC: 267 AN: 149014 Hom.: 0 Cov.: 30 AF XY: 0.00151 AC XY: 110 AN XY: 72612

Gnomad4 AFR AF: 0.000419

Gnomad4 AMR AF: 0.000542

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.00271

Gnomad4 NFE AF: 0.00311

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.000342 Hom.: 0

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:45 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 3 Pathogenic:16 Other:1

Pathogenic, no assertion criteria provided	curation	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Mar 06, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 27, 2017	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Sep 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: CNGB3 c.1148delC (p.Thr383IlefsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is a commonly known pathogenic variant. The variant allele was found at a frequency of 0.0017 in 250592 control chromosomes in the gnomAD database, including 2 homozygotes. c.1148delC has been reported in the literature in multiple individuals affected with Achromatopsia (eg. Michaelides_2004, Thiadens_2009, etc). 24 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All labs classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.175%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005225). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with achromatopsia 3 (MIM#262300) (PMIDs: 16379026, 23805033). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (489 heterozygotes, 2 homozygotes). The high prevalence of this variant is due to a founder effect in European populations (PMID: 17265047). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many individuals with achromatopsia in both homozygous and compound heterozygous states, and is thought to account for over 70% of all CNGB3-related achromatopsia cases (ClinVar, PMIDs: 25770143, 17265047). (SP) 1206 - This variant has been shown to be paternally inherited in a research setting. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 24, 2019	This variant was identified as homozygous -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3,PP4,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 05, 2024	- -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Thr383Ilefs*13) in the CNGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 28795510). This variant is present in population databases (rs397515360, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with achromatopsia (PMID: 10888875, 10958649, 15657609, 15712225, 17265047). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5225). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CNGB3: PVS1, PM2, PM3:Supporting, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that if a truncated CNGB3 protein is produced, then the resultant CNG channel complex leads to abnormal cone photoreceptor function (Peng et al., 2003; Liu et al., 2013); This variant is associated with the following publications: (PMID: 15657609, 17265047, 28041643, 22975760, 12815043, 16379026, 23805033, 20079539, 10888875, 28929832, 28341476, 29053603, 28746191, 29769798, 30609409, 30337596, 30190494, 30718709, 30418171, 31980526, 32036094, 32581362, 33546218, 32860008, 15712225, 28166811, 14757870, 34426522, 33851411, 32531858, 33562422, 33737949, 32037395) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Achromatopsia Pathogenic:7

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2015	The p.Thr383IlefsX13 (or p.Thr383fsX) (NM_019098.4 c.1148delC) variant in CNGB3 has been reported in >100 individuals with achromatopsia and was the most common CNGB3 variant identified in patients with this disease (Kohl 2003, Sundin 2010) . The reported patients were either homozygous or compound heterozygous with ano ther CNGB3 variant. This variant has been identified in 0.3% (187/66554) of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs397515360). Please note that for diseases with recessive inh eritance, clinical variability, or reduced penetrance pathogenic variants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 383 and leads to a premature termination codon 13 amino acids downs tream. This alteration is then predicted to lead to a truncated or absent protei n. Loss of function of the CNGB3 gene is an established disease mechanism in ind ividuals with achromatopsia. In summary, this variant meets our criteria to be c lassified as pathogenic for achromatopsia in an autosomal recessive manner based upon its segregation in affected individuals and predicted impact on protein fu nction. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Mar 20, 2018	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Leber congenital amaurosis Pathogenic:3

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

CNGB3-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 30, 2024	The CNGB3 c.1148delC variant is predicted to result in a frameshift and premature protein termination (p.Thr383Ilefs*13). This variant has been reported many times as causative for autosomal recessive achromatopsia (see for examples Kohl et al. 2005. PubMed ID: 15657609; Nishiguchi et al. 2005. PubMed ID: 15712225; Wiszniewski et al. 2007. PubMed ID: 17265047). This variant is reported in 0.28% of alleles in individuals of European (Finnish) descent and with a global allele frequency of 0.18% in gnomAD, indicating this variant is relatively common. Frameshift variants in CNGB3 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 07, 2018	The CNGB3 c.1148delC (p.Thr383IlefsTer13) variant results in a frameshift and is predicted to result in a premature termination of the protein. The p.Thr383IlefsTer13 variant has not been reported in the literature in individuals with Stargardt disease but is described as the most common pathogenic variant accounting for over 70% of all CNGB3 disease-causing alleles and approximately 40% of all achromatopsia-associated alleles (Wiszniewski et al 2007; Aboshiha et al. 2016). Across a selection of the available literature the p.Thr383IlefsTer13 variant is found in a total of 406 patients including 112 in a homozygous state, 41 in a compound heterozygous state, and eight in a heterozygous state (Sundin et al. 2000; Nishiguchi et al. 2005; Kohl et al. 2005; Wiszniewski et al. 2007). The p.Thr383IlefsTer13 variant showed segregation with disease. The variant was absent from 146 controls but is reported at a frequency of 0.00339 in the European American population of the Exome Sequencing Project. Wiszniewski et al. (2007) used haplotype analysis to demonstrate a founder effect among individuals of European ancestry for the variant thus explaining the high frequency. Functional studies showed that the p.Thr383IlefsTer13 variant resulted in a gain-of-function with enhanced channel activity and an increased sensitivity to cell death compared to wild type (Bright et al. 2005; Liu et al. 2013). Expression studies in Xenopus oocytes demonstrated that the p.Thr383IlefsTer13 variant failed to produce a CNGB3 subunit sufficient for normal cone photoreceptor function, and is essentially a null variant (Peng et al. 2003). Due to the potential impact of frameshift variants and the collective evidence from the literature, the p.Thr383IlefsTer13 variant is classified as a pathogenic variant for CNGB3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinal dystrophy Pathogenic:2

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 22, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2022

The c.1148delC (p.T383Ifs*13) alteration, located in exon 10 (coding exon 10) of the CNGB3 gene, consists of a deletion of one nucleotide at position 1148, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this alteration has an overall frequency of 0.18% (493/281708) total alleles studied. The highest observed frequency was 0.28% (71/25066) of European (Finnish) alleles. This is a common, recurrent mutation identified in multiple unrelated patients with achromatopsia in both the homozygous and compound heterozygous state (Sundin, 2000; Kohl, 2005; Wiszniewski, 2007; Mayer, 2017). The nucleotide position is prone to deletion and represents a mutational hotspot (Kohl, 2000). Based on the available evidence, this alteration is classified as pathogenic. -

Abnormality of the eye Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

Undetermined rare ocular disorder with frequency of less than eight patients -

Cone-rod dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397515360; hg19: chr8-87656008;