Submissions for variant NM_001297.5(CNGB1):c.413-1G>A

gnomAD frequency: 0.00010  dbSNP: rs189234741

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000504965	SCV000914732	likely pathogenic	Retinitis pigmentosa	2018-10-18	criteria provided, single submitter	clinical testing	The CNGB1 c.413-1G>A variant has been reported in three studies in at least four probands with retinitis pigmentosa, all in a homozygous state (Azam et al. 2011; Saqib et al. 2015; van Huet et al. 2015). Two of these probands were siblings and their unaffected parents were shown to carry the variant in a heterozygous state. Control data are not available for this variant which is reported at a frequency of 0.00024 in the South Asian population from the Exome Aggregation Consortium. When this variant was incorporated into a vector which was transfected into HeLa cells and retrotranscribed, the cDNA demonstrated a frameshift and introduction of a premature stop codon (Saqib et al. 2015). Based on the evidence and due to the potential impact of splice acceptor variants, the c.413-1G>A variant is classified as likely pathogenic for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056559	SCV001221009	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the CNGB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs189234741, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with retinitis pigmentosa (PMID: 25943428). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS6-1G>A. ClinVar contains an entry for this variant (Variation ID: 437976). Studies have shown that disruption of this splice site results in activation of a cryptic splice acceptor, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25943428). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074746	SCV001240341	pathogenic	Retinal dystrophy	2019-05-16	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000678544	SCV001573652	pathogenic	Retinitis pigmentosa 45	2021-04-08	criteria provided, single submitter	research	The CNGB1 c.413-1G>A 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: PVS1, PP1-M, PM3, PM2. Based on this evidence we have classified this variant as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000678544	SCV002815791	pathogenic	Retinitis pigmentosa 45	2024-05-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074746	SCV005073079	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504965	SCV000598716	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678544	SCV000804622	pathogenic	Retinitis pigmentosa 45	2016-09-01	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000504965	SCV001161025	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research