Submissions for variant NM_018451.5(CENPJ):c.2704C>T (p.Arg902Ter)

gnomAD frequency: 0.00003  dbSNP: rs374057641

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598603	SCV000709795	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614)
Illumina Laboratory Services, Illumina	RCV000778389	SCV000914618	uncertain significance	CENPJ-Related Disorders	2018-12-05	criteria provided, single submitter	clinical testing	The CENPJ c.2704C>T (p.Arg902Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant 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. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Invitae	RCV000598603	SCV002196502	pathogenic	not provided	2022-10-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 503612). This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. This variant is present in population databases (rs374057641, gnomAD 0.05%). This sequence change creates a premature translational stop signal (p.Arg902*) in the CENPJ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CENPJ are known to be pathogenic (PMID: 15793586, 16900296, 20522431).