Submissions for variant NM_000440.3(PDE6A):c.878C>T (p.Pro293Leu)

gnomAD frequency: 0.00309  dbSNP: rs114973968

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178770	SCV000230924	benign	not specified	2015-04-10	criteria provided, single submitter	clinical testing
Invitae	RCV000954915	SCV001101582	likely benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000787859	SCV001137003	benign	Retinitis pigmentosa	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000787859	SCV001315121	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.
CeGaT Center for Human Genetics Tuebingen	RCV000954915	SCV004157319	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003888635	SCV004706631	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787859	SCV000926874	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000954915	SCV001553642	likely benign	not provided		no assertion criteria provided	clinical testing	The PDE6A p.Pro293Leu variant was identified in the literature in two patients with retinitis pigementosa: in one case the variant was identfiied as a heterozygous variant with no second variant identified, and in the second case the variant was identified as a homozygous variant however the patient was also homozygous for the known pathogenic p.Val685Met variant (Dryja_1999_PMID: 10393062 and Anasagasti_2013_PMID: 24416769). The variant was identified in dbSNP (ID: rs114973968) and ClinVar (classified as benign by EGL Genetic Diagnostics and Mendelics, as likely benign by Invitae, and as likely pathogenic by Medical Genetics Laboratory Kennedy Center). The variant was identified in control databases in 904 of 282780 chromosomes (1 homozygous) at a frequency of 0.003197 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: European (non-Finnish) in 666 of 129142 chromosomes (freq: 0.005157), Other in 17 of 7226 chromosomes (freq: 0.002353), Latino in 81 of 35432 chromosomes (freq: 0.002286), South Asian in 65 of 30598 chromosomes (freq: 0.002124), European (Finnish) in 31 of 25114 chromosomes (freq: 0.001234), East Asian in 20 of 19952 chromosomes (freq: 0.001002), African in 20 of 24950 chromosomes (freq: 0.000802), and Ashkenazi Jewish in 4 of 10366 chromosomes (freq: 0.000386). Although the p.Pro293 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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	RCV000178770	SCV001918169	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000954915	SCV001963496	likely benign	not provided		no assertion criteria provided	clinical testing