ClinVar Genomic variation as it relates to human health

The p.Met2083Ile variant in DNAH5 has been reported in trans with a second DNAH5 variant (Met754Ilefs) in 1 individual with primary ciliary dyskinesia. Both var iants were present in 1 affected sibling (Knowles 2013). This variant has been identified in 1/66400 European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs753614861). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance , pathogenic variants may be present at a low frequency in the general populatio n. This variant affects the last base of the exon, which is part of the 5? splic e region, and has been shown to affect splicing (Knowles 2013). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Met2083Ile variant is likely pathogenic in an autosomal recessive fashi on

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2083 of the DNAH5 protein (p.Met2083Ile). This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. This variant is present in population databases (rs753614861, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 2127064, 2389146, 23261302). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228251). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 DNAH5 c.6249G>A (p.Met2083Ile) missense variant has been identified in a compound heterozygous state in six individuals from three families with primary ciliary dyskinesia and ciliary outer dynein arm defects demonstrated via electron microscopy (Berg et al. 2011; Knowles et al. 2013; Zariwala et al. 2013). Several of these individuals were reported to exhibit situs inversus, bronchiectasis, sinusitis and otitis media. Among these individuals, a sibling pair was shown to have inherited the variant from their healthy parent. Control data are unavailable for this variant, which is reported at a frequency of 0.000196 in the African population of the Genome Aggregation Database. RT-PCR of nasal RNA from one patient who carried a frameshift variant in trans with p.Met2083Ile demonstrated that the variant affects splicing, leading to two mutant transcripts, one showing deletion of exon 37 and the other deletion of exons 36 and 37. Both transcripts led to a premature translation termination signal (Knowles et al. 2013). Based on the collective evidence, the p.Met2083Ile variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Published functional studies demonstrate abnormal splicing leading to multiple aberrant transcripts (Knowles et al., 2013); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; In addition, in silico predictors suggest the missense change may have a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23261302, 21270641, 31879361, 23891469, 30067075, Poplawska_2021_Abstract)

The c.6249G>A pathogenic mutation (also known as p.M2083I), located in coding exon 37 of the DNAH5 gene, results from a G to A substitution at nucleotide position 6249. The methionine at codon 2083 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 37, which makes it likely to have some effect on normal mRNA splicing. This variant was described in two siblings with outer dynein arm defects detected by electron microscopy, and a frameshift alteration confirmed in trans. Studies demonstrated that this alteration leads to abnormal splicing and premature protein truncation (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106). In addition, this mutation was reported in two individuals with primary ciliary dyskinesia, both with situs inversus, outer dynein arm defects on electron microscopy, and a second DNAH5 alteration (Berg JS et al. Genet. Med., 2011 Mar;13:218-29; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.