ClinVar Genomic variation as it relates to human health

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: 20301301, 28199173, 30067075, 28801648, 32622824, 31980526, 34426522, 34569065, 24747639, 24824133, 33577779, 34210339, 34102041, 35804324, 26777464)

The p.Gln88ArgfsX8 variant in CCNO has been identified in at least 10 individuals with primary ciliary dyskinesia (PCD; 7 homozygotes, 3 compound heterozygotes) and segregated with disease in 7 affected individuals from 4 families (Wallmeier 2014, Casey 2015, Amirav 2016, Davis 2019). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 139600) and has been identified in 0.06% (10/17424) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 88 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CCNO gene is an established disease mechanism in autosomal recessive PCD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PCD. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong.

The frameshift c.258_262dup (p.Gln88ArgfsTer8) variant in CCNO gene has been reported previously in homozygous and compound heterozygous state in individuals affected with primary ciliary dyskinesia (Wallmeier et al. 2014; Casey et al. 2015; Davis et al. 2019). This variant segregated with disease in families consistently with autosomal recessive inheritance (Wallmeier et al. 2014). The p.Gln88ArgfsTer8 variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamine 88, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Gln88ArgfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Gln88Argfs*8) in the CCNO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCNO are known to be pathogenic (PMID: 24747639). This variant is present in population databases (rs587777502, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24747639, 24824133, 26777464). ClinVar contains an entry for this variant (Variation ID: 139600). For these reasons, this variant has been classified as Pathogenic.