Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000220262 | SCV000271356 | pathogenic | Primary ciliary dyskinesia | 2015-09-03 | criteria provided, single submitter | clinical testing | The p.Trp435X variant in DNAI2 has been reported in 3 Ashkenazi Jewish individua ls with PCD, all of whom were homozygous for the variant, and in 2 Caucasian sib lings with PCD, both of whom were compound heterozygous with a second pathogenic DNAI2 variant (Knowles 2013, Zariwala 2013). This variant has been identified i n 14/66582 European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs752924362). Please note that presence in the general population does not contradict pathogenicity, especially for recessive d isorders and disorders with reduced penetrance. This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a tr uncated or absent protein. In summary, this variant meets our criteria to be cla ssified as pathogenic for PCD in an autosomal recessive manner (http://www.partn ers.org/personalizedmedicine/LMM) based on multiple reports of this variant in i ndividuals with PCD and the predicted impact of the variant. |
Counsyl | RCV000410372 | SCV000487055 | pathogenic | Primary ciliary dyskinesia 9 | 2016-10-18 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000220262 | SCV000624446 | pathogenic | Primary ciliary dyskinesia | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp435*) in the DNAI2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAI2 are known to be pathogenic (PMID: 18950741, 23891469). This variant is present in population databases (rs752924362, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23261302, 23891469). ClinVar contains an entry for this variant (Variation ID: 228335). For these reasons, this variant has been classified as Pathogenic. |
Illumina Laboratory Services, |
RCV000410372 | SCV000914791 | likely pathogenic | Primary ciliary dyskinesia 9 | 2018-12-04 | criteria provided, single submitter | clinical testing | The DNAI2 c.1304G>A (p.Trp435Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp435Ter variant has been reported in one study and found in three individuals with primary ciliary dyskinesia, all in a homozygous state (Knowles et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.003376 in the Ashkenazi Jewish population of the Genome Aggregation Database. It is suggested that this variant may be a founder variant in the Ashkenazi Jewish population (Knowles et al. 2013; Fedick et al. 2015). Based on the potential impact of stop-gained variants and the clinical evidence, the p.Trp435Ter variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Fulgent Genetics, |
RCV000410372 | SCV002782505 | pathogenic | Primary ciliary dyskinesia 9 | 2022-02-25 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000220262 | SCV003992300 | pathogenic | Primary ciliary dyskinesia | 2023-05-30 | criteria provided, single submitter | clinical testing | The p.W435* pathogenic mutation (also known as c.1304G>A), located in coding exon 9 of the DNAI2 gene, results from a G to A substitution at nucleotide position 1304. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. This variant was identified in several individuals in the homozygous and compound heterozygous state with a clinical diagnosis or high clinical suspicion of primary ciliary dyskinesia (Zariwala MA et al. Am J Hum Genet, 2013 Aug;93:336-45; Knowles MR et al. Am J Hum Genet, 2013 Jan;92:99-106; Shoemark A et al. Eur Respir J, 2022 Nov;60:). It was also identified in the homozygous state in an individual with bronchiectasis (Gileles-Hillel A et al. ERJ Open Res, 2020 Oct;6:). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
Revvity Omics, |
RCV000410372 | SCV004234746 | pathogenic | Primary ciliary dyskinesia 9 | 2023-02-09 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000410372 | SCV000056626 | pathogenic | Primary ciliary dyskinesia 9 | 2013-01-10 | no assertion criteria provided | literature only | |
Natera, |
RCV000220262 | SCV001459509 | pathogenic | Primary ciliary dyskinesia | 2020-09-16 | no assertion criteria provided | clinical testing |