ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.1427_1428del (p.Phe476fs) (rs774493427)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671401 SCV000796374 likely pathogenic Ciliary dyskinesia, primary, 3 2017-12-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195305 SCV001365630 pathogenic Primary ciliary dyskinesia 2019-04-25 criteria provided, single submitter clinical testing The p.Phe476SerfsX26 variant in DNAH5 has been reported in the heterozygous state in 1 individual with primary ciliary dyskinesia and in the hemizygous state in 1 individual with Cri-du-Chat syndrome and features of primary ciliary dyskinesia who had a 5p13 deletion on the other allele (Hornef 2006, Shapiro 2014). It has also been identified in 0.002% (2/113524) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported as likely pathogenic in ClinVar (Variation ID 55559). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 476 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DNAH5 gene is an established disease mechanism in autosomal recessive primary ciliary dyskinesia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive primary ciliary dyskinesia. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting.
Invitae RCV001195305 SCV001391258 pathogenic Primary ciliary dyskinesia 2019-04-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe476Serfs*26) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual with clinical features of primary ciliary dyskinesia (PMID: 25066065). This variant is also known as 1426_1427del in the literature. ClinVar contains an entry for this variant (Variation ID: 555559). Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). For these reasons, this variant has been classified as Pathogenic.

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