Submissions for variant NM_000283.4(PDE6B):c.1726G>A (p.Gly576Ser)

gnomAD frequency: 0.00001  dbSNP: rs753925314

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479658	SCV000565364	likely pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29625443, 36460718, 30998820)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479658	SCV001413539	likely pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 576 of the PDE6B protein (p.Gly576Ser). This variant is present in population databases (rs753925314, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive PDE6B-related conditions (PMID: 29625443, 30998820). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 418401). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6B protein function. This variant disrupts the p.Gly576 amino acid residue in PDE6B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8595886; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV004794393	SCV005415528	likely pathogenic	Retinal dystrophy	2024-05-27	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004740254	SCV005363198	uncertain significance	PDE6B-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The PDE6B c.1726G>A variant is predicted to result in the amino acid substitution p.Gly576Ser. This variant was previously reported, along with a second missense variant in the same gene, in an individual with cone-rod dystrophy (Khateb et al. 2019. PubMed ID: 30998820), and in the homozygous state in an individual with retinal disease (supplementary data, Schlottmann et al. 2023. PubMed ID: 37217489). This variant was also reported in individuals with Usher syndrome or retinal disease, although no additional information was provided to help assess pathogenicity (supplementary data, Sun et al. 2018. PubMed ID: 29625443; supplementary data, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.