Submissions for variant NM_012144.4(DNAI1):c.1644G>A (p.Trp548Ter)

gnomAD frequency: 0.00006  dbSNP: rs200669099

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231603	SCV000289874	pathogenic	Primary ciliary dyskinesia	2024-06-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp548*) in the DNAI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAI1 are known to be pathogenic (PMID: 16858015, 29363216). This variant is present in population databases (rs200669099, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 16858015, 21270641). ClinVar contains an entry for this variant (Variation ID: 240854). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763195	SCV000893808	pathogenic	Kartagener syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000763195	SCV000916256	likely pathogenic	Kartagener syndrome	2018-10-31	criteria provided, single submitter	clinical testing	The DNAI1 c.1644G>A (p.Trp548Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp548Ter variant has been reported in a compound heterozygous state in two patients with neonatal respiratory distress and sinusitis as well as outer dynein arm defect on electron microscopy (Zariwala et al. 2006; Berg et al. 2011). Family studies for one patient found the p.Trp548Ter variant was inherited from the healthy father. The variant was absent from 113 control subjects and is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence in the literature and the potential impact of stop-gained variants, the p.Trp548Ter variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000231603	SCV001431609	pathogenic	Primary ciliary dyskinesia	2019-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000231603	SCV002704003	pathogenic	Primary ciliary dyskinesia	2018-03-08	criteria provided, single submitter	clinical testing	The p.W548* pathogenic mutation (also known as c.1644G>A), located in coding exon 17 of the DNAI1 gene, results from a G to A substitution at nucleotide position 1644. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This mutation was confirmed in trans with a second DNAI1 mutation in an individual with primary ciliary dykinesia and outer dynein arm defects on electron microscopy (Zariwala MA et al. Am. J. Respir. Crit. Care Med., 2006 Oct;174:858-66). 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.
Natera, Inc.	RCV000231603	SCV002085171	pathogenic	Primary ciliary dyskinesia	2020-12-14	no assertion criteria provided	clinical testing