NM_019098.5(CNGB3):c.1148del (p.Thr383fs) AND CNGB3-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 7, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000778111.7

Allele description [Variation Report for NM_019098.5(CNGB3):c.1148del (p.Thr383fs)]

NM_019098.5(CNGB3):c.1148del (p.Thr383fs)

Gene:

CNGB3:cyclic nucleotide gated channel subunit beta 3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_019098.5(CNGB3):c.1148del (p.Thr383fs)

Other names:

NP_061971.3:p.(Thr383IlefsTer13)

HGVS:

NC_000008.11:g.86643781del
NG_016980.1:g.104895del
NM_019098.5:c.1148delMANE SELECT
NP_061971.3:p.Thr383fs
NC_000008.10:g.87656009del
NC_000008.10:g.87656009delG
NM_019098.3:c.1148del
NM_019098.3:c.1148delC
NM_019098.4:c.1148delC
NM_019098.5:c.1148del
p.Thr383IlefsX13

Links:

OMIM: 605080.0002; dbSNP: rs397515360

NCBI 1000 Genomes Browser:

rs397515360

Molecular consequence:

NM_019098.5:c.1148del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: CNGB3-related disorder
Synonyms:: CNGB3-Related Disorders; CNGB3-related condition
Identifiers:: MedGen: CN239340

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000475215	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (May 7, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15712225, 23805033, 16379026, 17265047, 15657609, 25770143, 10888875, 12815043 Citation Link,
SCV004797053	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 7, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000475215

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(May 7, 2018)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV004797053

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 7, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases.

Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP.

Hum Mutat. 2005 Mar;25(3):248-58.

PubMed [citation]

PMID:: 15712225

Disease-associated mutations in CNGB3 promote cytotoxicity in photoreceptor-derived cells.

Liu C, Sherpa T, Varnum MD.

Mol Vis. 2013 Jun 11;19:1268-81. Print 2013.

PubMed [citation]

PMID:: 23805033
PMCID:: PMC3692405

See all PubMed Citations (9)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000475215.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV004797053.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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