Submissions for variant NM_000440.3(PDE6A):c.2275-1G>A

gnomAD frequency: 0.00006  dbSNP: rs1428612396

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064857	SCV001229784	pathogenic	not provided	2024-10-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 19 of the PDE6A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PDE6A are known to be pathogenic (PMID: 7493036, 22128245, 23847139). This variant is present in population databases (no rsID available, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 30029497; internal data). ClinVar contains an entry for this variant (Variation ID: 631962). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001064857	SCV004167875	likely pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign in association with PDE6A-related retinitis pigmentosa to our knowledge; This variant is associated with the following publications: (PMID: 31964843)
Illumina Laboratory Services, Illumina	RCV004808875	SCV005431534	pathogenic	Retinitis pigmentosa 43	2024-11-22	criteria provided, single submitter	clinical testing	The PDE6A c.2275-1G>A variant results in a substitution at the consensus splice acceptor site, which is predicted to result in splicing defects that may lead to a truncated protein. This variant has been identified in trans with a pathogenic variant in individuals with a phenotype consistent with retinitis pigmentosa. This variant is not observed at a significant frequency in version 4.1.0 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the evidence the c.2275-1G>A variant is classified as pathogenic for retinitis pigmentosa.
Illumina Laboratory Services, Illumina	RCV000778760	SCV000915125	uncertain significance	Retinitis pigmentosa	2018-10-31	flagged submission	clinical testing	The PDE6A c.2275-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is reported at a frequency of 0.000344 in the African population of the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.