Submissions for variant NM_001369.3(DNAH5):c.13775G>A (p.Arg4592Gln)

gnomAD frequency: 0.00014  dbSNP: rs367709427

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229430	SCV000287063	likely pathogenic	Primary ciliary dyskinesia	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4592 of the DNAH5 protein (p.Arg4592Gln). This variant is present in population databases (rs367709427, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of DNAH5-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 238964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAH5 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV000670498	SCV000452849	uncertain significance	Primary ciliary dyskinesia 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000670498	SCV000795355	uncertain significance	Primary ciliary dyskinesia 3	2017-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000229430	SCV002699508	uncertain significance	Primary ciliary dyskinesia	2015-07-30	criteria provided, single submitter	clinical testing	The p.R4592Q variant (also known as c.13775G>A), located in coding exon 79 of the DNAH5 gene, results from a G to A substitution at nucleotide position 13775. The arginine at codon 4592 is replaced by glutamine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs367709427. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles and 0.01% (1/8600) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since clinical data on this variant is limited at this time, its clinical significance is unclear.
Natera, Inc.	RCV000229430	SCV002078368	uncertain significance	Primary ciliary dyskinesia	2020-02-21	no assertion criteria provided	clinical testing