Submissions for variant NM_001369.3(DNAH5):c.4361G>A (p.Arg1454Gln)

gnomAD frequency: 0.00013  dbSNP: rs542708170

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000266533	SCV000341564	uncertain significance	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000477841	SCV000453168	uncertain significance	Primary ciliary dyskinesia 3	2016-07-11	criteria provided, single submitter	clinical testing	The DNAH5 c.4361G>A (p.Arg1454Gln) variant is a missense variant that has has been reported in four studies, all of which describe the same family of German origin (Olbrich et al. 2002; Olbrich et al. 2006; Loges et al. 2008; Raidt et al. 2014). The p.Arg1454Gln variant was found in a compound heterozygous state with a frameshift variant in two siblings with primary ciliary dyskinesia. The p.Arg1454Gln variant was absent from 200 control chromosomes (Olbrich et al. 2002) and is reported at a frequency of 0.00034 in the African population of the Exome Aggregation Consortium. Direct visualization of respiratory cells from the individuals carrying the variant showed an absence of cilia or membrane alterations. In the remaining ciliated cells, variant DNAH5 was absent from the ciliary axonemes and mislocalized to the basal body region (Olbrich et al. 2006; Loges et al. 2008). The evidence for this variant is limited. The p.Arg1454Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001247795	SCV001421238	likely pathogenic	Primary ciliary dyskinesia	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1454 of the DNAH5 protein (p.Arg1454Gln). This variant is present in population databases (rs542708170, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287698). 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 not expected to disrupt DNAH5 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV001247795	SCV002632248	pathogenic	Primary ciliary dyskinesia	2016-03-24	criteria provided, single submitter	clinical testing	The p.R1454Q variant (also known as c.4361G>A), located in coding exon 28 of the DNAH5 gene, results from a G to A substitution at nucleotide position 4361. The arginine at codon 1454 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in two siblings with primary ciliary dyskensia (characterized by outer dynein arm defects on electron microscopy) who were compound heterozygous for another DNAH5 mutation; both siblings had immotile cilia and one sibling had situs inversus (Olbrich H, Nat. Genet. 2002 Feb; 30(2):143-4; Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Ex vivo cultures of these patients' epithelial airway showed absent cilia or membrane alterations in many cells and mislocalization of DNAH5 to the basal body region in the remaining cells (Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Based on the available evidence, p.R1454Q is classified as a pathogenic mutation.
Molecular Genetics, Royal Melbourne Hospital	RCV001247795	SCV004812510	uncertain significance	Primary ciliary dyskinesia	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change in DNAH5 is predicted to replace arginine with glutamine at codon 1454, p.(Arg1454Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the coiled-coiled stem region. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (199/1,179,988 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been observed in trans with a pathogenic variant in two siblings with primary ciliary dyskinesia in a single family (PMID: 11788826, 25186273). It has conflicting interpretations in ClinVar (ID: 287698). Computational evidence is uninformative for the missense substitution (REVEL = 0.510). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP1.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477841	SCV000536778	likely pathogenic	Primary ciliary dyskinesia 3	2016-02-10	no assertion criteria provided	research
Natera, Inc.	RCV001247795	SCV002080949	uncertain significance	Primary ciliary dyskinesia	2020-01-17	no assertion criteria provided	clinical testing