Submissions for variant NM_019098.5(CNGB3):c.1208G>A (p.Arg403Gln)

gnomAD frequency: 0.00119  dbSNP: rs147876778

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000435881	SCV000225390	likely benign	not specified	2015-04-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000132679	SCV000512655	benign	not provided	2022-05-27	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000501136	SCV000588362	pathogenic	Abnormality of the eye	2017-06-18	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000597492	SCV000700212	pathogenic	Achromatopsia	2018-03-20	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000132679	SCV001105918	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164460	SCV001326587	likely benign	Severe early-childhood-onset retinal dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001164460	SCV001435146	likely benign	Severe early-childhood-onset retinal dystrophy		criteria provided, single submitter	research	The p.Arg403Gln variant in CNGB3 has been identified in 3 homozygous Pakistani individuals with progressive cone dystrophy, 1 homozygous Pakistani individual with complete achromatopsia, and in the heterozygous state in 1 individual with progressive cone dystrophy, segregated with eye disease in 4 relatives from 1 family (PMID: 15161866, 24504161), and has been identified in >2% of South Asian chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg403Gln variant may slightly impact protein function (PMID: 16379026). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive progressive cone dystrophy.
Genome-Nilou Lab	RCV000174144	SCV001737262	likely benign	Achromatopsia 3	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000435881	SCV003844722	uncertain significance	not specified	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: CNGB3 c.1208G>A (p.Arg403Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251014 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 24 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CNGB3 causing Achromatopsia (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Biallelic mutations in CNBG3 cause autosomal recessive Achromatopsia. However, the c.1208G>A variant has been reported in patients who present with a highly variable range of clinical findings from mild macular dystrophy to severe cone dystrophy with near complete loss of cone function (eg. Michaelides_2004, Lin_2017, Greenberg_2014, Jinda_2021, Burkard_2018, Mayer_2017). One in depth exploration of a large cohort of patients with the variant suggests the variant is a hypomorphic mutation that may cause relatively mild and late-onset or subclinical retinal disease in the homozygous state and may be a cause of digenic triallelic disease due to the correlation of disease severity with CNGB3 and CNGA3 genoytpes (Burkard_2018). Consistent with the clinical findings, a Cngb3-R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3/) mice to obtain triallelic Cnga3+/ Cngb3R403Q/R403Q mutants showed striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice (Burkard_2018). A different functional study found that co-expression of WT CNGA3 and mutant CNGB3/p.R403Q in Xenopus oocytes resulted in formation of heterotetrameric CNG channels with normal surface expression, but increased apparent ligand sensitivity and increased outward rectification, suggesting a gain-of-function mechanism (Bright_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16379026, 30418171, 24504161, 32869108, 28418496, 28795510, 15161866, 37734845). ClinVar contains an entry for this variant (Variation ID: 143154). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000132679	SCV003917614	benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	CNGB3: BS1, BS2
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132679	SCV000172631	probable-non-pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Likely benign.
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000174144	SCV000575809	likely pathogenic	Achromatopsia 3	2017-03-27	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678546	SCV000804624	uncertain significance	Retinitis pigmentosa	2016-09-01	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000597492	SCV001161027	pathogenic	Achromatopsia	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV000597492	SCV001455000	uncertain significance	Achromatopsia	2020-01-08	no assertion criteria provided	clinical testing