Submissions for variant NM_201548.5(CERKL):c.316C>A (p.Arg106Ser)

dbSNP: rs569826109

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001071725	SCV001237043	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 106 of the CERKL protein (p.Arg106Ser). This variant is present in population databases (rs569826109, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of inherited retinal dystrophy (PMID: 18978954; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438054). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg106 amino acid residue in CERKL. Other variant(s) that disrupt this residue have been observed in individuals with CERKL-related conditions (PMID: 28838317), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001277034	SCV001573374	likely pathogenic	Retinitis pigmentosa 26	2021-04-08	criteria provided, single submitter	research	The CERKL c.316C>A 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: PP1, PM3, PM2, PM5. Based on this evidence we have classified this variant as Likely Pathogenic.
GeneDx	RCV001071725	SCV001989518	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18978954, 28041643, 24735978, 32411380, 19667359, 33322828, 34315337)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001277034	SCV002768953	pathogenic	Retinitis pigmentosa 26	2022-03-31	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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (highest allele: 16 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional nuclear localization signal sequence (KLKRR) (PMID: 19501188). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to a cysteine has been reported in individuals with cone-rod dystrophy (ClinVar, PMID: 29068140). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with retinitis pigmentosa (ClinVar, PMID: 18978954, 34315337). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a large Parkistani family (PMID: 18978954). (SP) 1002 - This variant has limited functional evidence supporting abnormal protein function. CERKL has been proven to modulate the oxidation of TRX2, a mitochondria-specific regulator of redox balance and apoptosis. In vitro studies using GST pull-down assay has shown that this variant significantly reduced the binding of CERKL and TRX2 (PMID: 24735978). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226314	SCV003922759	pathogenic	Retinitis pigmentosa	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: CERKL c.316C>A (p.Arg106Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 249812 control chromosomes, predominantly at a frequency of 0.00043 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CERKL causing Retinitis Pigmentosa (5.2e-05 vs 0.0013), allowing no conclusion about variant significance. c.316C>A has been reported in the literature as a biallelic genotype in multiple individuals affected with retinal dystrophies and was shown to segregate with disease in at least one family (e.g. Ali_2008, Downes_2020, Duzkale_2021). These data indicate that the variant is very likely to be associated with disease. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Five classified the variant as pathogenic (n=2)/likely pathogenic (n=3) and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001277034	SCV004216778	likely pathogenic	Retinitis pigmentosa 26	2023-10-25	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504821	SCV000598881	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001277034	SCV001463769	likely pathogenic	Retinitis pigmentosa 26	2020-09-16	no assertion criteria provided	clinical testing