Submissions for variant NM_001369.3(DNAH5):c.13458dup (p.Asn4487Ter)

dbSNP: rs775696136

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000377034	SCV000452932	likely pathogenic	Primary ciliary dyskinesia	2016-06-14	criteria provided, single submitter	clinical testing	The c.13458dupT (p.Asn4487Ter) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Asn4487Ter variant has been reported in one patient with primary ciliary dyskinesia in a homozygous state, and three patients in a compound heterozygous state with a second missense or frameshift variant (Hornef et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.00070 in the African American population of the Exome Sequencing Project. Based on the evidence and the potential impact of frameshift variants, the p.Asn4487Ter variant is classified as likely pathogenic for primary ciliary dyskinesia.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000377034	SCV000624219	pathogenic	Primary ciliary dyskinesia	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn4487*) 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 present in population databases (rs775696136, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 21270641). ClinVar contains an entry for this variant (Variation ID: 350995). For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000377034	SCV001334259	pathogenic	Primary ciliary dyskinesia	2020-04-01	criteria provided, single submitter	research
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000377034	SCV001431583	likely pathogenic	Primary ciliary dyskinesia	2018-11-08	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001257126	SCV001433658	pathogenic	Primary ciliary dyskinesia 3	2019-12-18	criteria provided, single submitter	clinical testing	This DNAH5 variant (rs775696136) has been identified in the homozgyous or compound heterozgygous state in multiple patients with primary ciliary dyskinesia. It is rare in population datasets (gnomAD: 16/251312 total alleles; 0.006367%; no homozygotes). Two submitters to ClinVar have classified DNAH5 c.13458dupT as either likely pathogenic or pathogenic. This frameshift variant results in a premature stop codon in exon 77 of 79 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic.
GeneDx	RCV001565222	SCV001788529	pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31638833, 34791246, 34758253, 24498942, 31980526, 31589614, 33635012, 35753512, 21270641, 30293990, 16627867, 31879361)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001257126	SCV002048083	pathogenic	Primary ciliary dyskinesia 3	2021-08-20	criteria provided, single submitter	clinical testing	The DNAH5 c.13458dupT; p.Asn4487Ter variant (rs775696136) is reported in the literature in the homozygous or compound heterozygous state in nine individuals affected with primary ciliary dyskinesia (Hornef 2006, Fassad 2020). This variant is also reported in ClinVar (Variation ID: 350995). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (13/113666 alleles) in the Genome Aggregation Database. This variant results in an early termination codon and is predicted to results in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Hornef N et al. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. 2006 Jul 15;174(2):120-6. PMID: 16627867. Fassad MR et al. Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. J Med Genet. 2020 May;57(5):322-330. PMID: 31879361.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001257126	SCV002557263	pathogenic	Primary ciliary dyskinesia 3	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Primary ciliary dyskinesia 3 (MIM#608644). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 16 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with primary ciliary dyskinesia, both homozygotes and compound heterozygotes (ClinVar, PMID: 33635012). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV000377034	SCV002688791	pathogenic	Primary ciliary dyskinesia	2020-11-19	criteria provided, single submitter	clinical testing	The c.13458dupT pathogenic mutation (also known as p.N4487* and c.13458_13459insT), located in coding exon 77 of the DNAH5 gene, results from a duplication of T at nucleotide position 13458. This changes the amino acid from an asparagine to a stop codon within coding exon 77. This alteration was first identified in 4 families with PCD; it was detected in conjunction with another pathogenic mutation in 3 families and in the homozygous state in 1 family (Hornef N et al. Am. J. Respir. Crit. Care Med. 2006; 174:120-6). This alteration was also identified in conjunction with a deletion of exon 62 in a 16 year old female with PCD; this individual had a history of neonatal respiratory distress, situs inversus, bronchiectasis, sinusitis, frequent otitis media, significantly reduced nasal nitric oxide, and outer dyenin arm defects on electron microscopy (Berg JS et al. Genet. Med. 2011; 13:218-29). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV001257126	SCV002807428	pathogenic	Primary ciliary dyskinesia 3	2024-03-07	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001565222	SCV005197749	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000377034	SCV001462278	pathogenic	Primary ciliary dyskinesia	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001257126	SCV001760149	pathogenic	Primary ciliary dyskinesia 3		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742395	SCV005360125	pathogenic	DNAH5-related disorder	2024-05-21	no assertion criteria provided	clinical testing	The DNAH5 c.13458dupT variant is predicted to result in premature protein termination (p.Asn4487*). This variant has been reported in the homozygous or compound heterozygous state in individuals with primary ciliary dyskinesia (see, for example, Hornef et al. 2006. PubMed ID: 16627867; Quinlan-Jones et al. 2018. PubMed ID: 30293990; Fassad et al. 2019. PubMed ID: 31879361). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense variants in DNAH5 are expected to be pathogenic. This variant is interpreted as pathogenic.