Submissions for variant NM_018718.3(CEP41):c.976C>T (p.Arg326Ter)

gnomAD frequency: 0.00001  dbSNP: rs782286004

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778820	SCV000915210	uncertain significance	Joubert syndrome 15	2018-10-31	criteria provided, single submitter	clinical testing	The CEP41 c.976C>T (p.Arg326Ter) variant is a stop-gained variant, which was observed by ICSL 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 for this variant, it 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. No publications were found based on this search. This variant is located in the last exon and may escape nonsense-mediated decay. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, the p.Arg326Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for Joubert syndrome.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778820	SCV001513771	uncertain significance	Joubert syndrome 15	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg326*) in the CEP41 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the CEP41 protein. This variant is present in population databases (rs782286004, gnomAD 0.009%). 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: 631996). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.