ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.9449del (p.Gly3150fs) (rs727504802)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156128 SCV000205842 likely pathogenic Primary ciliary dyskinesia 2013-11-08 criteria provided, single submitter clinical testing The Gly3150fs variant in DNAH5 has not been previously identified in individuals with pulmonary disease nor has it been identified in large population studies. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 3150 and lead to a premature termination codon 24 amino ac ids downstream. This alteration is then predicted to lead to a truncated or abse nt protein. Frameshift and other truncating variants in DNAH5 are associated wit h autosomal recessive primary ciliary dyskinesia (PCD) with outer dynein arm (OD A) defects (Olbrich 2002, Hornef 2006, Ferkol 2013). In summary, this variant is likely pathogenic, though additional studies are required to fully establish it s clinical significance.
GeneDx RCV000492880 SCV000582721 pathogenic not provided 2015-09-23 criteria provided, single submitter clinical testing The c.9449delG deletion in the DNAH5 gene has been reported previously in an individual with confirmed PCD who harbored this variant in the heterozygous state, without a second identifiable variant in this gene; sequence analysis of 11 other PCD related genes in this individual was negative (Kim et al., 2014). The c.9449delG variant causes a frameshift starting with codon Glycine 3150, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Gly3150AlafsX24. This deletion is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Frameshift and other protein truncating variantsdownstream of this deletion have been reported in the Human Gene Mutation Database in association with PCD (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. The c.9449delG deletion was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.9449delG as a pathogenic variant.
Invitae RCV000156128 SCV000942569 pathogenic Primary ciliary dyskinesia 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly3150Alafs*24) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with primary ciliary dyskinesia (PCD) (PMID: 24498942 ) and also has been observed in combination with another DNAH5 variant in an individual with PCD (Invitae). 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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