Submissions for variant NM_001277115.2(DNAH11):c.10691+2T>C

gnomAD frequency: 0.00001  dbSNP: rs886039341

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254927	SCV000321559	uncertain significance	not provided	2019-04-30	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon(s) [3523-3564]; This variant is associated with the following publications: (PMID: 26633542)
Illumina Laboratory Services, Illumina	RCV000778827	SCV000915218	uncertain significance	Primary ciliary dyskinesia 7	2017-10-02	criteria provided, single submitter	clinical testing	The DNAH11 c.10691+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL 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 for this variant, it 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 and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for primary ciliary dyskinesia.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000778827	SCV001164095	pathogenic	Primary ciliary dyskinesia 7	2020-02-27	criteria provided, single submitter	clinical testing
Invitae	RCV002518749	SCV003504704	pathogenic	Primary ciliary dyskinesia	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change affects donor splice site in intron 65 of the DNAH11 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 33608380). ClinVar contains an entry for this variant (Variation ID: 265100). Studies have shown that disruption of this splice site results in activation of cryptic splice sites and introduces a premature termination codon (PMID: 33608380). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.