ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.10615C>T (p.Arg3539Cys) (rs1304504006)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000629442 SCV000750384 likely pathogenic Primary ciliary dyskinesia 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3539 of the DNAH5 protein (p.Arg3539Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with a second, rare DNAH5 variant in several individuals affected with primary ciliary dyskinesia (PMID: 19357118, 23891469) and has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with primary ciliary dyskinesia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Arg3539 amino acid residue in DNAH5 have been observed in affected individuals (PMID: 22316021, 24498942, 22499950, 26373788). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

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