Submissions for variant NM_018451.5(CPAP):c.1586C>G (p.Ser529Ter)

gnomAD frequency: 0.00029  dbSNP: rs202058504

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145556	SCV000192649	pathogenic	Microcephaly 6, primary, autosomal recessive	2013-02-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762912	SCV000893324	likely pathogenic	Microcephaly 6, primary, autosomal recessive; Seckel syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
DASA	RCV000145556	SCV002588764	pathogenic	Microcephaly 6, primary, autosomal recessive	2022-11-03	criteria provided, single submitter	clinical testing	The c.1586C>G;p.(Ser529*) variant creates a premature translational stop signal in the CENPJ gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (Clinvar ID: 158194) - PS4_supporting. The variant is present at low allele frequencies population databases (rs202058504 – gnomAD 0.001169%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002466446	SCV003488973	pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser529*) 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). This variant is present in population databases (rs202058504, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. ClinVar contains an entry for this variant (Variation ID: 158194). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology	RCV000145556	SCV004801811	likely pathogenic	Microcephaly 6, primary, autosomal recessive		criteria provided, single submitter	clinical testing	A previously undescribed nucleotide variant creates a premature translation stop signal p.Ser529Ter in the CENPJ gene. The variant was observed in presumably compound heterozygous state with another LoF variant (phase not tested) in an individual affected with microcephaly and micrognathia. Homozygous and compound heterozygous variants are reported in patients with Microcephaly 6, primary, autosomal recessive, 608393, and Seckel syndrome 4, 613676. The variant is present in gnomAD population database at low frequency (24/250986 chromosomes, no homozygotes). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000145556	SCV001432342	pathogenic	Microcephaly 6, primary, autosomal recessive		no assertion criteria provided	clinical testing
GeneDx	RCV002466446	SCV002762195	uncertain significance	not provided	2022-06-08	flagged submission	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)