Submissions for variant NM_001369.3(DNAH5):c.5503C>T (p.Gln1835Ter)

gnomAD frequency: 0.00001  dbSNP: rs761622153

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413667	SCV000490515	likely pathogenic	not provided	2016-04-05	criteria provided, single submitter	clinical testing	The Q1835X variant in the DNAH5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q1835X variant 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. Therefore, we interpret Q1835X as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539827	SCV000624269	uncertain significance	Primary ciliary dyskinesia	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1835*) 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 (rs761622153, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a copy number gain of DNAH5 exon 1-50. In all individuals where phase was determined, the p.Gln1835* variant and the exon 1-50 copy number gain were on the same chromosome. As a result, it is unknown which copy of the DNAH5 gene this variant is located in, or how this variant impacts gene function. (Invitae). ClinVar contains an entry for this variant (Variation ID: 372356). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV001283848	SCV001520031	pathogenic	Primary ciliary dyskinesia 3	2020-06-11	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001283848	SCV001984196	pathogenic	Primary ciliary dyskinesia 3	2020-02-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001283848	SCV002021718	pathogenic	Primary ciliary dyskinesia 3	2023-08-11	criteria provided, single submitter	clinical testing
Human Genetics Section, Sidra Medicine	RCV001283848	SCV004708154	pathogenic	Primary ciliary dyskinesia 3	2024-02-28	criteria provided, single submitter	research	Loss of function is a known mechanism of disease in DNAH5 related primary ciliary dyskinesia (MIM#608644). Extremely low frequency in gnomAD population databases (Total allele frequency 0.000007985). ClinVar contains an entry for this variant (Variation ID: 372356). The variant is heterozygous in 4 siblings with primary ciliary dyskinesia. We thus classify the variant as pathogenic
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001283848	SCV004806638	likely pathogenic	Primary ciliary dyskinesia 3	2024-03-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001283848	SCV005668909	pathogenic	Primary ciliary dyskinesia 3	2024-04-05	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001283848	SCV001469281	uncertain significance	Primary ciliary dyskinesia 3	2020-10-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742412	SCV005352185	likely pathogenic	DNAH5-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The DNAH5 c.5503C>T variant is predicted to result in premature protein termination (p.Gln1835*). This variant has been previously reported in an individual with primary ciliary dyskinesia (Al-Dewik et al. 2019. PubMed ID: 30919572, Supplementary Table 1). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in DNAH5 are expected to be pathogenic. This variant is interpreted as likely pathogenic.