ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Thr277Argfs*3) in the CCDC39 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs773801386, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 2325550, 23891469). ClinVar contains an entry for this variant (Variation ID: 242176). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The CCDC39 c.830_831delCA (p.Thr277ArgfsTer3) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Thr277ArgfsTer3 variant has been reported in three studies and was found in a total of six individuals with primary ciliary dyskinesia, including in two in a homozygous state and in four in a compound heterozygous state, although three of the compound heterozygous probands were members of the same family (Antony et al. 2013; Zariwala et al. 2013; Kim et al. 2014). The homozygous individual reported by Antony et al. (2013) also had three unaffected family members who carried the variant in a heterozygous state. Control data are unavailable for this variant. The highest reported frequency for the variant in the Exome Sequencing Project is 0.00828 in the African American population. However, this frequency is orders of magnitude higher than the highest frequency reported in the Exome Aggregation Consortium, where the p.Thr277ArgfsTer3 variant is found at a frequency of 0.00008 in the European (non-Finnish population). Due to the difficulty in calling indels, the frequency of this variant in the Exome Sequencing Project, which is inconsistent with the disease prevalence, is not considered reliable. Based on the evidence, including the potential impact of truncating frameshift variants, the p.Thr277ArgfsTer3 variant is considered to be likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.830_831delCA pathogenic mutation, located in coding exon 7 of the CCDC39 gene, results from a deletion of two nucleotides at nucleotide positions 830 to 831, causing a translational frameshift with a predicted alternate stop codon (p.T277Rfs*3). This mutation has been identified in the homozygous and compound heterozygous state in several individuals with primary ciliary dyskinesia (Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Davis SD et al. Am J Respir Crit Care Med, 2019 Jan;199:190-198). In addition to the clinical data presented in the literature, yhis alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Observed with a pathogenic variant on the opposite allele (in trans) as well as in the homozygous state in association with primary ciliary dyskinesia in several patients in the published literature (PMID: 23891469, 23255504, 30067075); Frameshift 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; This variant is associated with the following publications: (PMID: 24498942, 31589614, 23255504, 31879361, 30067075, 35942088, 36809189, 36593399, 23891469)

Variant summary: CCDC39 c.830_831delCA (p.Thr277ArgfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.830_831delCA has been reported in the literature in at-least one individual affected with Primary ciliary dyskinesia (example, Kim_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24498942). ClinVar contains an entry for this variant (Variation ID: 242176). Based on the evidence outlined above, the variant was classified as pathogenic.