Submissions for variant NM_001369.3(DNAH5):c.13774C>T (p.Arg4592Ter)

gnomAD frequency: 0.00001  dbSNP: rs758112779

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001376959	SCV001574167	pathogenic	Primary ciliary dyskinesia	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg4592*) in the DNAH5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the DNAH5 protein. This variant is present in population databases (rs758112779, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 32502767; Invitae). ClinVar contains an entry for this variant (Variation ID: 1066064). This variant disrupts a region of the DNAH5 protein in which other variant(s) (p.Cys4621Tyr) have been observed in individuals with DNAH5-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001376959	SCV002573555	likely pathogenic	Primary ciliary dyskinesia	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001376959	SCV002699506	uncertain significance	Primary ciliary dyskinesia	2019-06-07	criteria provided, single submitter	clinical testing	The p.R4592* variant (also known as c.13774C>T), located in coding exon 79 of the DNAH5 gene, results from a C to T substitution at nucleotide position 13774. This changes the amino acid from an arginine to a stop codon within coding exon 79. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of DNAH5, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 33 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002493914	SCV002803259	likely pathogenic	Primary ciliary dyskinesia 3	2022-04-25	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002493914	SCV004171832	likely pathogenic	Primary ciliary dyskinesia 3		criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001376959	SCV002078369	likely pathogenic	Primary ciliary dyskinesia	2021-07-28	no assertion criteria provided	clinical testing