ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.10815del (p.Pro3606fs) (rs397515540)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206560 SCV000261040 pathogenic Primary ciliary dyskinesia 2020-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro3606Hisfs*23) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397515540, ExAC 0.02%). This variant has been reported in the literature in individuals affected with primary ciliary dyskinesia (PMID: 16627867, 23477994, 24498942, 22416021). ClinVar contains an entry for this variant (Variation ID: 65636). Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724843 SCV000700856 pathogenic not provided 2017-01-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000055849 SCV000915114 pathogenic Ciliary dyskinesia, primary, 3 2016-10-17 criteria provided, single submitter clinical testing The DNAH5 c.10815delT (p.Pro3606HisfsTer23) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Pro3606HisfsTer23 variant has been reported in a total of 17 individuals with primary ciliary dyskinesia, including in two in a homozygous state and in 15 in a compound heterozygous state (Hornef et al. 2006; Djakow et al. 2012; Ferkol et al. 2013; Kim et al. 2014; Raidt et al. 2014). The p.Pro3606HisfsTer23 variant was found to segregate with disease where familial DNA was available, and haplotype analysis revealed this variant is a founder mutation (Hornef et al. 2006). The p.Pro3606HisfsTer23 variant was absent from 70 controls and is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Pro3606HisfsTer23 variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000724843 SCV001168574 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing The c.10815delT variant in the DNAH5 gene has been reported previously in association with autosomal recessive primary ciliary dyskinesia when present in the homozygous state or when in trans with another disease-causing variant and is considered a North American founder pathogenic variant (Hornef et al., 2006). The c.10815delT variant causes a frameshift starting with codon Proline 3606, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.P3606HfsX23. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.10815delT variant is observed in 43/126,216 (0.034%) alleles from individuals of European (Non-Finnish) background in large population cohorts (Lek et al., 2016). We interpret c.10815delT as a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000055849 SCV001364290 pathogenic Ciliary dyskinesia, primary, 3 2020-03-26 criteria provided, single submitter research ACMG codes: PVS1, PM3, PP4, PP5
GeneReviews RCV000055849 SCV000086845 pathologic Ciliary dyskinesia, primary, 3 2011-09-15 no assertion criteria provided curation Converted during submission to Pathogenic.

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