Submissions for variant NM_201548.5(CERKL):c.950G>A (p.Arg317His)

gnomAD frequency: 0.00004  dbSNP: rs150587104

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001141153	SCV001162448	pathogenic	Retinitis pigmentosa	2020-01-09	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV001141153	SCV001301479	uncertain significance	Retinitis pigmentosa	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805969	SCV002051338	uncertain significance	not specified	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: CERKL c.1028G>A (p.Arg343His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250930 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CERKL causing Retinitis Pigmentosa (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1028G>A has been reported in the literature in a homozygous individual affected with sporadic retinitis pigmentosa (Weisschuh_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and one laboratory classified the variant as pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549229	SCV003459202	uncertain significance	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 343 of the CERKL protein (p.Arg343His). This variant is present in population databases (rs150587104, gnomAD 0.03%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 32531858). ClinVar contains an entry for this variant (Variation ID: 813162). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CERKL protein function with a positive predictive value of 95%. This variant disrupts the p.Arg343 amino acid residue in CERKL. Other variant(s) that disrupt this residue have been observed in individuals with CERKL-related conditions (PMID: 36819107), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.