Submissions for variant NM_001369.3(DNAH5):c.10384C>T (p.Gln3462Ter)

gnomAD frequency: 0.00004  dbSNP: rs571919972

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233866	SCV000287050	pathogenic	Primary ciliary dyskinesia	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln3462*) 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 (rs571919972, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 22416021, 23891469, 24498942). ClinVar contains an entry for this variant (Variation ID: 238953). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000679863	SCV000807229	pathogenic	Primary ciliary dyskinesia 3	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another missense variant in a 14-year-old female with chronic lung disease, AV malformations, chylopericardium and pulmonary lymphangiectasia, skin nevi, absent puberty.
Fulgent Genetics, Fulgent Genetics	RCV000679863	SCV002811615	pathogenic	Primary ciliary dyskinesia 3	2024-05-28	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000233866	SCV004812514	pathogenic	Primary ciliary dyskinesia	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change in DNAH5 is a nonsense variant predicted to cause a premature stop codon, p.(Gln3462*), in biologically relevant exon 61/79 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.008% (90/1,180,028 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been detected in the homozygous and compound heterozygous state in multiple individuals with primary ciliary dyskinesia, confirmed in trans in at least one of these individuals (PMID: 22416021, 25186273, 23891469, 29363216, 37860582). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PM2_Supporting.
Ambry Genetics	RCV000233866	SCV005573148	pathogenic	Primary ciliary dyskinesia	2024-09-09	criteria provided, single submitter	clinical testing	The p.Q3462* pathogenic mutation (also known as c.10384C>T), located in coding exon 61 of the DNAH5 gene, results from a C to T substitution at nucleotide position 10384. This changes the amino acid from a glutamine to a stop codon within coding exon 61. This variant has been identified in the homozygous state and/or in conjunction with other DNAH5 variant(s) in individuals with features consistent with primary ciliary dyskinesia; in at least one instance, the variants were identified in trans (Djakow J et al. Pediatr Pulmonol, 2012 Sep;47:864-75; Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Raidt J et al. Eur Respir J, 2014 Dec;44:1579-88; Paff T et al. Hum Mutat, 2018 May;39:653-665; Fassad MR et al. J Med Genet, 2020 May;57:322-330). 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.	RCV000233866	SCV001452265	pathogenic	Primary ciliary dyskinesia	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001572953	SCV001798094	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001572953	SCV001807072	pathogenic	not provided		no assertion criteria provided	clinical testing