Submissions for variant NM_001369.3(DNAH5):c.9449del (p.Gly3150fs)

dbSNP: rs727504802

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000156128	SCV000942569	pathogenic	Primary ciliary dyskinesia	2023-05-02	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. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 179339). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004742284	SCV005361052	pathogenic	DNAH5-related disorder	2024-08-23	no assertion criteria provided	clinical testing	The DNAH5 c.9449delG variant is predicted to result in a frameshift and premature protein termination (p.Gly3150Alafs*24). This variant was reported in an individual with primary ciliary dyskinesia (PCD) as the only detected DNAH5 variant, while testing of other PCD related genes was negative (Kim et al 2014. PubMed ID: 24498942). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in DNAH5 are expected to be pathogenic. This variant is interpreted as pathogenic.