ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.6249G>A (p.Met2083Ile) (rs753614861)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000214042 SCV000271213 likely pathogenic Primary ciliary dyskinesia 2016-02-24 criteria provided, single submitter clinical testing 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
Invitae RCV000214042 SCV000287091 pathogenic Primary ciliary dyskinesia 2020-01-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 2083 of the DNAH5 protein (p.Met2083Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. It also falls at the last nucleotide of exon 37 of the DNAH5 coding sequence. This variant is present in population databases (ExAC 0.002%). This variant has been reported as a causative allele in multiple individuals affected with primary ciliary dyskinesia (PMID: 23261302, 2127064, 2389146). In one family this variant was determined to be on the opposite chromosome of a pathogenic frameshift in two affected siblings (PMID: 23261302). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare variant with uncertain impact on mRNA splicing and protein function that has been reported to segregate with disease in multiple affected individuals. For these reasons, it has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778755 SCV000915119 likely pathogenic Ciliary dyskinesia, primary, 3 2017-09-18 criteria provided, single submitter clinical testing 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.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000214042 SCV001431585 likely pathogenic Primary ciliary dyskinesia 2018-11-08 criteria provided, single submitter clinical testing
OMIM RCV000778755 SCV000056623 pathogenic Ciliary dyskinesia, primary, 3 2013-01-10 no assertion criteria provided literature only

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