Submissions for variant NM_001364171.2(ODAD1):c.853G>A (p.Ala285Thr)

gnomAD frequency: 0.00022  dbSNP: rs147718607

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231978	SCV000291388	pathogenic	Primary ciliary dyskinesia	2024-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 248 of the CCDC114 protein (p.Ala248Thr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs147718607, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23261302, 23261303). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in the use of a cryptic splice donor site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23261302). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000032837	SCV000893540	pathogenic	Primary ciliary dyskinesia 20	2022-02-16	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000231978	SCV001431737	pathogenic	Primary ciliary dyskinesia	2019-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001579702	SCV002543953	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000231978	SCV002755180	pathogenic	Primary ciliary dyskinesia	2017-12-20	criteria provided, single submitter	clinical testing	The c.742G>A pathogenic mutation (also known as p.A248T), located in coding exon 6 of the CCDC114 gene, results from a G to A substitution at nucleotide position 742. The amino acid change results in alanine to threonine at codon 248, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This mutation was identified in muliple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous state (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106; Onoufriadis A et al. Am. J. Hum. Genet., 2013 Jan;92:88-98; Boaretto F et al. J Mol Diagn, 2016 Nov;18:912-922). In addition, analysis of RNA from affected individuals homozygous for this alteration showed an insertion of 79 nucleotides, resulting in premature protein truncation (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106; Onoufriadis A et al. Am. J. Hum. Genet., 2013 Jan;92:88-98). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001579702	SCV003761925	pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Reported as a common pathogenic variant among individuals of Dutch Volendam background (Onoufriadis et al., 2013; Kos et al., 2022); Non-canonical splice site variant demonstrated to result in loss of function (Onoufriadis et al., 2013); This variant is associated with the following publications: (PMID: 23261303, 20301301, 23261302, 35163670, 35343062)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000032837	SCV005876493	pathogenic	Primary ciliary dyskinesia 20	2024-02-16	criteria provided, single submitter	clinical testing	The ODAD1 c.742G>A; p.Ala248Thr variant (rs147718607) is reported in the literature in several compound heterozygous and homozygous individuals and families affected with primary ciliary dyskinesia (Boaretto 2016, Knowles 2013, Kos 2022, Onoufriadis 2013). This variant is a known founder variant in the Dutch - Volendam population (Kos 2022, Onoufriadis 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 39637), and is found in the non-Finnish European population with an allele frequency of 0.05% (60/128,802 alleles) in the Genome Aggregation Database (v2.1.1). This missense variant disrupts the consensus donor splice site of exon 7, and RNA analysis of homozygous individuals showed the use of a cryptic splice site and introduction of a premature termination codon (Knowles 2013, Onoufriadis 2013). Based on available information, this variant is considered to be pathogenic. References: Boaretto F et al. Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients. J Mol Diagn. 2016 Nov;18(6):912-922. PMID: 27637300. Knowles MR et al. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):99-106. PMID: 23261302. Kos R et al. Primary ciliary dyskinesia in Volendam: Diagnostic and phenotypic features in patients with a CCDC114 mutation. Am J Med Genet C Semin Med Genet. 2022 Mar;190(1):89-101. PMID: 35343062. Onoufriadis A et al. Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):88-98. PMID: 23261303.
OMIM	RCV000032837	SCV000056606	pathogenic	Primary ciliary dyskinesia 20	2013-01-10	no assertion criteria provided	literature only
GeneReviews	RCV000190918	SCV000245804	not provided	Kartagener syndrome		no assertion provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579702	SCV001808187	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579702	SCV001951692	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579702	SCV001964177	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754279	SCV005352163	pathogenic	ODAD1-related disorder	2024-08-23	no assertion criteria provided	clinical testing	The ODAD1 c.742G>A variant is predicted to result in the amino acid substitution p.Ala248Thr. This variant has been reported to segregate in multiple families with primary ciliary dyskinesia and laterality defects in the Dutch Volendam population, and is believed to be a founder mutation (Onoufriadis et al. 2013. PubMed ID: 23261303; Knowles et al. 2013. PubMed ID: 23261302). The c.742G base is the terminal nucleotide of exon 7 and alterations of this base have been shown to disrupt the adjacent GT donor site, resulting in a frameshift and premature protein termination (Onoufriadis et al. 2013. PubMed ID: 23261303; Knowles et al. 2013. PubMed ID: 23261302). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.