Submissions for variant NM_133497.4(KCNV2):c.778A>T (p.Lys260Ter)

gnomAD frequency: 0.00003  dbSNP: rs139027297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255665	SCV000322296	pathogenic	not provided	2017-11-17	criteria provided, single submitter	clinical testing	The K260X variant in the KCNV2 gene has been reported previously in association with retinal cone dystrophy in one sibling pair and a third unrelated individual who were heterozygous for the K260X variant and heterozygous for a second loss-of-function variant in the KCNV2 gene (Thiagalingam et al., 2007; Wissinger et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The K260X variant was not observed at any significant frequency in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret K260X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255665	SCV001231120	pathogenic	not provided	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys260*) 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 present in population databases (rs139027297, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cone dystrophy (PMID: 17896311, 21882291). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265419). For these reasons, this variant has been classified as Pathogenic.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324523	SCV004030418	pathogenic	Cone dystrophy	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816466	SCV005069107	pathogenic	Retinal dystrophy	2014-01-01	criteria provided, single submitter	clinical testing