Submissions for variant NM_133497.4(KCNV2):c.427G>T (p.Glu143Ter)

dbSNP: rs104894113

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV000003146	SCV002023236	pathogenic	Cone dystrophy with supernormal rod response	2021-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851603	SCV002129903	pathogenic	not provided	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu143*) in the KCNV2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNV2 are known to be pathogenic (PMID: 16909397, 18235024). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of KCNV2-related conditions (PMID: 16909397, 31960170). ClinVar contains an entry for this variant (Variation ID: 3010). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001851603	SCV003927549	pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing	Identified in individuals with cone dystrophy with supernormal rod response in published literature (Wu et al., 2006); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31725702, 31960170, 21900228, 23105016, 32552793, 32783370, 16909397)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000003146	SCV004807886	likely pathogenic	Cone dystrophy with supernormal rod response	2024-03-23	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000003146	SCV005420864	pathogenic	Cone dystrophy with supernormal rod response	2024-10-04	criteria provided, single submitter	research	PVS1,PM2,PM3(strong)
OMIM	RCV000003146	SCV000023304	pathogenic	Cone dystrophy with supernormal rod response	2006-09-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000003146	SCV001469227	likely pathogenic	Cone dystrophy with supernormal rod response	2020-06-07	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751194	SCV005353737	pathogenic	KCNV2-related disorder	2024-04-08	no assertion criteria provided	clinical testing	The KCNV2 c.427G>T variant is predicted to result in premature protein termination (p.Glu143*). This variant has been characterized as a founder mutation in Arabian populations and has been reported in the homozygous state in multiple individuals with retinal cone dystrophy 3B (a.k.a., cone dystrophy with supernormal rod response; CDSRR) (Wu et al. 2006. PubMed ID: 16909397; Khan et al. 2012. PubMed ID: 21900228; Abu-Safieh et al. 2013. PubMed ID: 23105016; Khan 2019. PubMed ID: 31725702; Abdelkader et al. 2020. PubMed ID: 31960170; Méjécase et al. 2020. PubMed ID: 32783370). This variant has also been reported in the presumed compound heterozygous state in an individual with a second disease-causing KCNV2 variant and has been observed to co-segregate with disease in a large family (Wu et al. 2006. PubMed ID: 16909397). This variant has not been reported in the gnomAD database, indicating this variant is rare. Nonsense variants in KCNV2 are expected to be pathogenic. This variant is interpreted as pathogenic.