Submissions for variant NM_201548.5(CERKL):c.967_968del (p.Met323fs)

gnomAD frequency: 0.00001  dbSNP: rs750151209

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008158	SCV001167919	pathogenic	not provided	2019-09-23	criteria provided, single submitter	clinical testing	Frameshift 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 a significant frequency in large population cohorts (Lek et al., 2016); Observed in homozygous state in several unrelated patients in published literature (Ellingford et al., 2016; Biswas et al., 2017) and not observed in homozygous state in controls
Invitae	RCV001008158	SCV001229160	pathogenic	not provided	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met349Valfs*20) in the CERKL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CERKL are known to be pathogenic (PMID: 14681825, 23591405, 24043777). This variant is present in population databases (rs750151209, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with CERKL-related disease (PMID: 27208204, 28130426, 28838317). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236491). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000225454	SCV001240070	pathogenic	Retinal dystrophy	2017-09-15	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001277031	SCV001573406	pathogenic	Retinitis pigmentosa 26	2021-04-08	criteria provided, single submitter	research	The CERKL c.1045_1046del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PP1-S, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001277031	SCV002767072	pathogenic	Retinitis pigmentosa 26	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 26 (MIM#608380). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have been reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with retinitis pigmentosa (ClinVar, PMID: 28130426, 27208204, 28838317). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV001277031	SCV004216784	pathogenic	Retinitis pigmentosa 26	2023-10-19	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225454	SCV000282601	likely pathogenic	Retinal dystrophy		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001277031	SCV001463766	pathogenic	Retinitis pigmentosa 26	2020-09-16	no assertion criteria provided	clinical testing