Submissions for variant NM_001369.3(DNAH5):c.12367C>T (p.His4123Tyr)

gnomAD frequency: 0.00019  dbSNP: rs151145750

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253565	SCV000307691	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094958	SCV000452966	uncertain significance	Primary ciliary dyskinesia 3	2018-01-12	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	RCV000361695	SCV000624207	likely benign	Primary ciliary dyskinesia	2025-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000361695	SCV002666620	benign	Primary ciliary dyskinesia	2017-02-09	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001094958	SCV005879936	uncertain significance	Primary ciliary dyskinesia 3	2024-11-15	criteria provided, single submitter	clinical testing	The DNAH5 c.12367C>T; p.His4123Tyr variant (rs151145750, ClinVar Variation ID: 257996) is reported in the literature in three individuals affected with laterality defects/heterotaxy; however, no additional evidence of causality was presented (Kosaki 2020, Li 2018, Liu 2022). This variant is found in the East Asian population with an allele frequency of 1.0% (207/19,922 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.341). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Kosaki R et al. Consecutive medical exome analysis at a tertiary center: Diagnostic and health-economic outcomes. Am J Med Genet A. 2020 Jul;182(7):1601-1607. PMID: 32369273. Li S et al. A novel ZIC3 gene mutation identified in patients with heterotaxy and congenital heart disease. Sci Rep. 2018 Aug 17;8(1):12386. PMID: 30120289 Liu S et al. LOF variants identifying candidate genes of laterality defects patients with congenital heart disease. PLoS Genet. 2022 Dec 2;18(12):e1010530. PMID: 36459505
Natera, Inc.	RCV000361695	SCV002078399	benign	Primary ciliary dyskinesia	2020-01-24	no assertion criteria provided	clinical testing