Submissions for variant NM_001297.5(CNGB1):c.3560G>A (p.Arg1187Gln)

gnomAD frequency: 0.00004  dbSNP: rs543712958

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000364070	SCV000398296	uncertain significance	Retinitis pigmentosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358311	SCV001725236	benign	not provided	2025-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522880	SCV003745772	likely benign	Inborn genetic diseases	2022-08-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358311	SCV001554011	likely benign	not provided		no assertion criteria provided	clinical testing	The CNGB1 p.Arg1181Gln variant was not identified in the literature but was identified in dbSNP (ID: rs543712958), ClinVar (classified as uncertain significance by Illumina) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 276 of 269178 chromosomes (1 homozygous) at a frequency of 0.001025 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 253 of 30428 chromosomes (freq: 0.008315), Other in 2 of 6942 chromosomes (freq: 0.000288), European (non-Finnish) in 19 of 120534 chromosomes (freq: 0.000158) and African in 2 of 22564 chromosomes (freq: 0.000089), but was not observed in the Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Arg1181 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV001358311	SCV001918140	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001358311	SCV001965613	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922352	SCV004739694	benign	CNGB1-related disorder	2019-07-03	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).