Submissions for variant NM_006204.4(PDE6C):c.1004+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003062291	SCV003441542	likely pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with cone-rod dystrophy (PMID: 23776498). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change affects a donor splice site in intron 6 of the PDE6C 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 PDE6C are known to be pathogenic (PMID: 19887631, 23776498, 26103963, 30080950).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225999	SCV003922190	likely pathogenic	Cone dystrophy 4	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.1004+1G>A variant in PDE6C was identified by our study, in the compound heterozygous state with a likely pathogenic variant (NC_000010.11:g.93658917del), in an individual with cone-rod dystrophy. This individual also carried a likely pathogenic variant (NC_000010.11:g.93658917del), however the phase of these variants are unknown at this time. The c.1004+1G>A variant in PDE6C has been previously reported in 3 unrelated individuals with cone dystrophy 4 (PMID: 30080950, PMID: 23776498, PMID: 26992781), but has been identified in 0.02% (1/5196) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs958171434). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 3 affected individuals, two were homozygotes (PMID: 30080950, PMID: 23776498) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 26992781; ClinVar Variation ID: 835028), which increases the likelihood that the c.1004+1G>A variant is pathogenic. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PDE6C gene is an established disease mechanism in autosomal recessive cone dystrophy 4. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cone dystrophy 4. ACMG/AMP Criteria applied: PVS1, PM3 (Richards 2015).