Submissions for variant NM_001277115.2(DNAH11):c.9376G>A (p.Glu3126Lys)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002287999	SCV002578507	uncertain significance	not provided	2022-04-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with a second DNAH11 missense variant with primary ciliary dyskinesia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Nakhleh et al., 2012); This variant is associated with the following publications: (PMID: 22499950)
Ambry Genetics	RCV002373079	SCV002686401	uncertain significance	Primary ciliary dyskinesia	2014-08-01	criteria provided, single submitter	clinical testing	The p.E3133K variant (also known as c.9397G>A), located in coding exon 57 of the DNAH11 gene, results from a G to A substitution at nucleotide position 9397. The glutamic acid at codon 3133 is replaced by lysine, an amino acid with similar properties. This alteration was first reported in an individual who had a history of newborn respiratory distress, otits media, recurrent pneumonia, bronchiectasis and congenital heart disease; a second alteration in DNAH11 was also identfied (p.Q1507P), however, the phase (cis/trans) of the alterations is not known (Nakhleh Net al. Circulation. 2012;125(18):2232-42). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6041 samples (12082 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging but tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002373079	SCV003278201	benign	Primary ciliary dyskinesia	2024-12-04	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051956	SCV005685161	uncertain significance	Primary ciliary dyskinesia 7	2024-07-23	criteria provided, single submitter	clinical testing	The DNAH11 c.9376G>A (p.Glu3126Lys), also described as c.9397G>A (p.Glu3313Lys), has been reported in one patient affected with primary ciliary dyskinesia who carried a second DNAH11 missense variant with unknown phase (Nakhleh N et al., PMID: 22499950). This variant is only observed 15/279,642 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on DNAH11 function. This variant has been reported in the ClinVar database as a germline variant of uncertain significance by two submitters and benign by one submitter. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.