ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.661G>A (p.Val221Met) (rs1085307485)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489466 SCV000576555 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing The c.661 G>A variant in the DNAH5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.661 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.661 G>A may damage the natural splice acceptor site in intron 6 that could. However, in the absence of RNA/functional studies, the actual effect of the c.661 G>A change in this individual is unknown. If c.661 G>A does not alter splicing, it will result in the V221M missense change. The V221M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret c.661 G>A as a variant of uncertain significance.
Invitae RCV000693540 SCV000821413 uncertain significance Primary ciliary dyskinesia 2018-01-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 221 of the DNAH5 protein (p.Val221Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DNAH5-related disease. ClinVar contains an entry for this variant (Variation ID: 426176). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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