Submissions for variant NM_001369.3(DNAH5):c.1715T>G (p.Leu572Trp)

gnomAD frequency: 0.00067  dbSNP: rs137878131

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000765816	SCV000453266	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000336304	SCV000546346	benign	Primary ciliary dyskinesia	2024-01-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765816	SCV000897206	uncertain significance	Primary ciliary dyskinesia 3	2022-05-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825330	SCV000966625	uncertain significance	not specified	2018-03-22	criteria provided, single submitter	clinical testing	The p.Leu572Trp variant in DNAH5 has not been previously reported in individuals with primary ciliary dyskinesia, but has been identified in 0.1% (147/120780) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs13787813). Computational prediction tools and conse rvation analysis suggest that the p.Leu572Trp variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Leu572Trp variant is uncertain. ACMG/A MP Criteria applied: PP3.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000336304	SCV001431756	uncertain significance	Primary ciliary dyskinesia	2018-10-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000765816	SCV001716376	uncertain significance	Primary ciliary dyskinesia 3	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001770279	SCV001993471	uncertain significance	not provided	2024-06-07	criteria provided, single submitter	clinical testing	Identified in a patient with primary ciliary dyskinesia in published literature, however additional genotype and phenotype information was not provided (Nothe-Menchen et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 35737725, 29402277, 31638833, 37860582)
Ambry Genetics	RCV000336304	SCV002714721	likely benign	Primary ciliary dyskinesia	2022-05-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000765816	SCV004177021	uncertain significance	Primary ciliary dyskinesia 3	2023-09-12	criteria provided, single submitter	clinical testing	The DNAH5 c.1715T>G (p.Leu572Trp) variant has been reported in one individual with Kartagener’s syndrome, but was not determined to be causative (Ozkavukcu S et al., PMID: 29402277). Additionally, DNAH5 c.1715T>G was published in an individual with situs inversus, but the protein change reported is p.Leu573*, so it is unclear if this is the same variant or a report of a distinct variant (Nöthe-Menchen T et al., PMID: 31638833). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.1% in the European (non-Finnish) population, which is consistent with carrier status of primary ciliary dyskinesia. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to DNAH5 function. 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.
Breakthrough Genomics, Breakthrough Genomics	RCV001770279	SCV005189431	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000336304	SCV001462740	uncertain significance	Primary ciliary dyskinesia	2019-12-16	no assertion criteria provided	clinical testing