Submissions for variant NM_000283.4(PDE6B):c.794G>A (p.Arg265Gln)

gnomAD frequency: 0.00084  dbSNP: rs144562730

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178068	SCV000230058	uncertain significance	not provided	2015-04-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000288799	SCV000450772	benign	Congenital stationary night blindness autosomal dominant 2	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000346036	SCV000450773	uncertain significance	Retinitis pigmentosa	2018-01-12	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	RCV000178068	SCV001117384	likely benign	not provided	2025-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000178068	SCV001550037	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PDE6B p.Arg265Gln variant was identified in a compound heterozygous patient with retinitis pigmentosa from a cohort of 99 patients with inherited retinal dystrophies and 21 healthy relatives (Bernardis_2016_PMID:28127548). The variant was identified in dbSNP (ID: rs144562730) and ClinVar (classified as likely benign by Illumina and uncertain significance by EGL Genetics). The variant was identified in control databases in 302 of 282448 chromosomes (2 homozygous) at a frequency of 0.001069 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 70 of 30614 chromosomes (freq: 0.002287), European (non-Finnish) in 193 of 128836 chromosomes (freq: 0.001498), Other in 7 of 7214 chromosomes (freq: 0.00097), Latino in 22 of 35436 chromosomes (freq: 0.000621), Ashkenazi Jewish in 4 of 10352 chromosomes (freq: 0.000386), African in 5 of 24930 chromosomes (freq: 0.000201) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Arg265 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics, Academic Medical Center	RCV000178068	SCV001924693	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000178068	SCV001956223	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000178068	SCV001969685	uncertain significance	not provided		no assertion criteria provided	clinical testing