Submissions for variant NM_018718.3(CEP41):c.754G>A (p.Gly252Arg)

gnomAD frequency: 0.00009  dbSNP: rs201834429

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443886	SCV000534768	uncertain significance	not provided	2018-11-26	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CEP41 gene. The G252R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G252R variant is observed in 9/18774 (0.05%) alleles from individuals of East Asian background (Lek et al., 2016). The G252R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV001163694	SCV001325758	uncertain significance	Joubert syndrome 15	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001163694	SCV002316158	uncertain significance	Joubert syndrome 15	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 252 of the CEP41 protein (p.Gly252Arg). This variant is present in population databases (rs201834429, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CEP41-related conditions. ClinVar contains an entry for this variant (Variation ID: 391647). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CEP41 protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV002522643	SCV003633506	uncertain significance	Inborn genetic diseases	2022-11-10	criteria provided, single submitter	clinical testing	The c.754G>A (p.G252R) alteration is located in exon 9 (coding exon 9) of the CEP41 gene. This alteration results from a G to A substitution at nucleotide position 754, causing the glycine (G) at amino acid position 252 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.