ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.7998G>T (p.Glu2666Asp) (rs148720124)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665929 SCV000790140 uncertain significance Ciliary dyskinesia, primary, 3 2017-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000766289 SCV000589412 uncertain significance not provided 2016-05-13 criteria provided, single submitter clinical testing The E2666D variant in the DNAH5 gene has been reported previously in the heterozygous state in one individual with idiopathic, non-syndromic reduced sperm motility (Zuccarello et al., 2008). While not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports E2666D was observed in 22/8600 (0.25%) alleles from individuals of European American background, indicating it may be a rare variant in this population. The E2666D 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 that is conserved 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 E2666D as a variant of uncertain significance.
Invitae RCV000168168 SCV000218830 uncertain significance Primary ciliary dyskinesia 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 2666 of the DNAH5 protein (p.Glu2666Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs148720124, ExAC 0.2%). This variant has been reported in an individual affected with asthenozoospermia (PMID: 18492703). ClinVar contains an entry for this variant (Variation ID: 188229). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000218415 SCV000271691 uncertain significance not specified 2015-06-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Glu2666Asp va riant in DNAH5 has been reported in 1 heterozygous Caucasian individual with iso lated asthenozoospermia (Zuccarello 2008). It has also been identified in 0.2% ( 115/66240) of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs148720124). Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein. In summary, while the clinical significance of the p.Glu2666As p variant is uncertain, its frequency suggests that it is more likely to be beni gn.

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