Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000463290 | SCV000550928 | pathogenic | Primary ciliary dyskinesia | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 500 of the DNAAF5 protein (p.Cys500Phe). This variant is present in population databases (rs144405450, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 29358401, 29363216). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410302). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAAF5 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DNAAF5 function (PMID: 29358401). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV000764723 | SCV000895858 | uncertain significance | Primary ciliary dyskinesia 18 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000463290 | SCV002702283 | likely pathogenic | Primary ciliary dyskinesia | 2019-09-17 | criteria provided, single submitter | clinical testing | The p.C500F variant (also known as c.1499G>T), located in coding exon 7 of the DNAAF5 gene, results from a G to T substitution at nucleotide position 1499. The cysteine at codon 500 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been described homozygous in a pair of siblings with primary ciliary dyskinesia as well as two siblings in a second family in conjunction with a frameshift mutation, but phase was not specified in the latter (Horani A et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:E1221-E1228; Paff T et al. Hum. Mutat., 2018 05;39:653-665). In addition, functional studies of the p.C500F homozygous patients' nasal epithelial cells showed increased HEATR2-SPAG1 protein aggregates as well as misfolded proteins involved in the preassembly complex, which the authors suggest could cause instability; however; information on the sequencing of other involved genes were not available (Horani A et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:E1221-E1228). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Gene |
RCV003235226 | SCV003932961 | likely pathogenic | not provided | 2023-06-09 | criteria provided, single submitter | clinical testing | Identified with a second variant (phase unknown) in individuals with primary ciliary dyskinesia referred for genetic testing at GeneDx and in published literature (Paff et al., 2018); Published functional studies in mice demonstrate a damaging effect which results in cilia defects, reduced cilia motility, and developmental abnormalities (Horani et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358401, 36712068, 29363216) |
| Genetics and Molecular Pathology, |
RCV000764723 | SCV004175456 | likely pathogenic | Primary ciliary dyskinesia 18 | 2023-07-04 | criteria provided, single submitter | clinical testing | The DNAAF5 c.1499G>T variant is classified as Likely Pathogenic (PM2, PM3, PP1_Supporting, PS3_Supporting) The DNAAF5 c.1499G>T variant is a single nucleotide change in exon 7/13 of the DNAAF5 gene, which is predicted to change the amino acid cysteine at position 500 in the protein to phenylalanine. The variant is rare in population databases (gnomAD allele frequency = 0.011%; 18 het and 0 hom in 152,244 sequenced alleles) (PM2). The variant has been reported in dbSNP (rs144405450), the HGMD database as disease causing (CM184879) and with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 410302). It has been reported in the literature in a pair of siblings with PCD who also harboured a DNAAF5 frameshift variant, however the phase was not specified (PMID: 29363216). The variant has been reported in the homozygous state in two siblings affected by PCD (PMID: 29358401) (PM3, PP1_Supporting). The homozygous siblings both showed mild sinusitis, mild otitis media and absent inner/outer dynein arms on TEM. The proband also presented with situs inversus. Functional studies by the authors using patients' nasal epithelial cells showed a detrimental effect on protein function (PS3_Supporting). |
| Johns Hopkins Genomics, |
RCV000764723 | SCV004239031 | likely pathogenic | Primary ciliary dyskinesia 18 | 2023-12-14 | criteria provided, single submitter | clinical testing | This DNAAF5 missense variant has been reported in the compound heterozygous and homozygous states in individuals with primary ciliary dyskinesia, and has also been shown to segregate with disease . It (rs144405450) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 319/1608784 total alleles; 0.02%; no homozygotes), and has been reported in ClinVar (Variation ID 410302). Two bioinformatic tools queried predict that this substitution would be damaging, and the cysteine residue at this position is evolutionarily conserved across all of the species assessed. Additionally, functional studies support the prediction that this variant is deleterious, although these findings are insufficient to make a conclusion at this time. We consider c.1499G>T in DNAAF5 to be likely pathogenic. |
| OMIM | RCV000764723 | SCV000992449 | pathogenic | Primary ciliary dyskinesia 18 | 2019-09-12 | no assertion criteria provided | literature only |