Submissions for variant NM_001297.5(CNGB1):c.2957A>T (p.Asn986Ile)

gnomAD frequency: 0.00116  dbSNP: rs201162411

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000504912	SCV000398309	pathogenic	Retinitis pigmentosa	2017-08-25	criteria provided, single submitter	clinical testing	The CNGB1 c.2957A>T (p.Asn986Ile) missense variant has been reported in two studies in which it is found in six unrelated individuals with an autosomal recessive form of retinitis pigmentosa, including in four in a homozygous state and in two in a compound heterozygous state (Simpson et al. 2011; Hull et al. 2017). Common phenotypes in these individuals included night blindness with an onset in infancy or childhood, loss of peripheral vision in adulthood, and based on a fundus exam, a majority of patients had optic disc pallor, retinal pigment epithelium atrophy, and intraretinal pigment migration. The two individuals with the variant in a compound heterozygous state also had affected siblings with the same variants, one affected sister in one family and an additional affected brother and sister in the second family (Hull et al. 2017). The p.Asn986Ile variant was absent from 720 control chromosomes (Simpson et al. 2011) and is reported at a frequency of 0.00652 in the European (Finnish) population of the Genome Aggregation Database. Based on the clinical evidence, the p.Asn986Ile variant is classified as pathogenic for an autosomal recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000153040	SCV001207500	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 986 of the CNGB1 protein (p.Asn986Ile). This variant is present in population databases (rs201162411, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 21147909, 28041643, 28056120, 28559085, 29912909). 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: 166891). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CNGB1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073599	SCV001239150	pathogenic	Retinal dystrophy	2019-07-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000153040	SCV001245983	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000153040	SCV001480162	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331891	SCV001524040	pathogenic	Retinitis pigmentosa 45	2020-01-15	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001331891	SCV001573449	likely pathogenic	Retinitis pigmentosa 45	2021-04-08	criteria provided, single submitter	research	The CNGB1 c.2957A>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS4, PM3, PP1, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic.
GeneDx	RCV000153040	SCV001813463	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23105016, 32483926, 32531858, 28056120, 26355662, 21147909, 29912909, 23977260, 24015210, 29068140, 28559085, 28041643, 30718709, 31725169, 31456290, 33465333, 34426522, 31570810, 33576794, 33847019, 32037395)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000504912	SCV001950241	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Asn986Ile variant in CNGB1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS4, PM3, PP1, PP3, PP5. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity	RCV001331891	SCV003821260	pathogenic	Retinitis pigmentosa 45	2022-03-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907442	SCV004726627	pathogenic	CNGB1-related disorder	2024-01-03	criteria provided, single submitter	clinical testing	The CNGB1 c.2957A>T variant is predicted to result in the amino acid substitution p.Asn986Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with retinitis pigmentosa (see for example, Table 2, Simpson et al. 2011. PubMed ID: 21147909; Table S1, Stone et al. 2017. PubMed ID: 28559085; Table S4, Jespersgaard et al. 2019. PubMed ID: 30718709). This variant is reported in 0.64% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001331891	SCV004807265	uncertain significance	Retinitis pigmentosa 45	2024-03-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000504912	SCV004848473	pathogenic	Retinitis pigmentosa	2021-01-27	criteria provided, single submitter	clinical testing	The p.Asn986Ile variant in CNGB1 has been reported in multiple individuals with retinitis pigmentosa, all of whom were homozygous or compound heterozygous with a second CNGB1 variant (Simpson 2011, PMID: 21147909; Abu-Safieh 2013, PMID: 23105016; Carss 2017, PMID: 28041643; Stone 2017, PMID: 28559085; Hull 2017, PMID: 28056120; Fuster-Garcia 2019, PMID: 31725169; Jespersgaad 2019, PMID: 30718709; Radojevic 2020, DOI: 10.1080/13816810.2020.1832532). This variant also segregated with disease in 6 affected individuals from 5 families (Hull, 2017, PMID: 28056120; Fuster-Garcia, 2019, PMID: 31725169; Radojevic, 2020, DOI: 10.1080/13816810.2020.1832532). This variant has been identified in 0.635% (159/25032) of European (Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org) with no cases of homozygosity and a frequency low enough to be consistent with a recessive allele frequency for this gene. This variant has also been reported in ClinVar (Variation ID 166891). Computational prediction tools and conservation analyses support that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PP3.
Eurofins Ntd Llc (ga)	RCV000153040	SCV000202494	uncertain significance	not provided	2014-04-27	flagged submission	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504912	SCV000598713	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504912	SCV000926547	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000504912	SCV001161021	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Faculty of Health Sciences, Beirut Arab University	RCV001257781	SCV001434644	pathogenic	Autosomal recessive retinitis pigmentosa	2015-09-10	no assertion criteria provided	literature only