Submissions for variant NM_006205.3(PDE6H):c.35C>G (p.Ser12Ter)

gnomAD frequency: 0.00012  dbSNP: rs200311463

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779093	SCV000915582	likely pathogenic	PDE6H-related disorder	2018-08-23	criteria provided, single submitter	clinical testing	The PDE6H c.35C>G (p.Ser12Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Ser12Ter variant has been reported in two studies and is found in a homozygous state in five probands from three families including two sibling pairs (Kohl et al. 2012; Pedurupillay et al. 2016). Three of the probands are diagnosed with incomplete achromatopsia and two with cone dystrophy. The unaffected parents of the siblings were confirmed heterozygotes for the p.Ser12Ter variant. The p.Ser12Ter variant was absent from 180 control subjects and is reported at a frequency of 0.000166 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants and evidence from the literature, the p.Ser12Ter variant is classified as likely pathogenic for PDE6H-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV001092385	SCV001248872	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092385	SCV002227721	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser12*) in the PDE6H gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDE6H are known to be pathogenic (PMID: 22901948, 27472364). This variant is present in population databases (rs200311463, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with achromatopsia (PMID: 22901948, 27472364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37245). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Heidelberg University	RCV000055928	SCV002556342	likely pathogenic	Retinal cone dystrophy 3A	2022-05-23	criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV004794348	SCV005415534	pathogenic	Retinal dystrophy	2024-05-27	criteria provided, single submitter	research
OMIM	RCV000030807	SCV000053478	pathogenic	Achromatopsia 6	2012-09-07	no assertion criteria provided	literature only
GeneReviews	RCV000055928	SCV000086940	not provided	Retinal cone dystrophy 3A		no assertion provided	literature only
Department of Medical Genetics, Oslo University Hospital	RCV000055928	SCV000256082	pathogenic	Retinal cone dystrophy 3A	2015-10-27	no assertion criteria provided	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000055928	SCV001369732	uncertain significance	Retinal cone dystrophy 3A	2019-12-04	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092385	SCV001957650	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001092385	SCV001971195	pathogenic	not provided		no assertion criteria provided	clinical testing