Submissions for variant NM_018718.3(CEP41):c.851G>A (p.Arg284Gln)

gnomAD frequency: 0.00003  dbSNP: rs782105300

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000426821	SCV000536335	uncertain significance	not provided	2017-01-17	criteria provided, single submitter	clinical testing	The c.851G>A variant in the CEP41 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In-silico splice prediction models predict that c.851G>A may create a cryptic splice acceptor site in exon 10, however the natural splice acceptor site in intron 9 is unaffected. In the absence of RNA/functional studies, the actual effect of c.851G>A change in this individual is unknown. If c.851G>A does not alter splicing, it will result in the R284Q missense change. The R284Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.851G>A as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322686	SCV001513570	uncertain significance	Joubert syndrome 15	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 284 of the CEP41 protein (p.Arg284Gln). This variant is present in population databases (rs782105300, gnomAD 0.03%). 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: 392987). 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 not expected to disrupt CEP41 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000426821	SCV002497565	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing