Submissions for variant NM_001277115.2(DNAH11):c.1426-2A>G

dbSNP: rs1064794014

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481858	SCV000567586	pathogenic	not provided	2015-08-27	criteria provided, single submitter	clinical testing	The c.1426-2A>G variant in the DNAH11 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Furthermore, the c.1426-2A>G variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.1426-2A>G as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766672	SCV004674708	likely pathogenic	Primary ciliary dyskinesia	2023-01-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the DNAH11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAH11 are known to be pathogenic (PMID: 18022865, 20513915, 22184204). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 419646). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV005252908	SCV005907636	likely pathogenic	Primary ciliary dyskinesia 7	2025-02-11	criteria provided, single submitter	curation	The c.1426-2A>G variant in DNAH11 has not been previously reported in the literature in individuals with primary ciliary dyskinesia, but has been identified in 0.00008% (1/1176692) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1064794014). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 419646) and has been interpreted as pathogenic by GeneDx and likely pathogenic by Invitae. This variant is located in the 5' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 1 base from the intron-exon boundary, providing evidence that this variant may cause a frameshift and lead to a premature termination codon downstream. This alteration is then predicted to lead to a truncated or absent protein. However, this information is not predictive enough to determine pathogenicity. Loss of function of the DNAH11 gene is an established disease mechanism in autosomal recessive primary ciliary dyskinesia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive primary ciliary dyskinesia. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015).