Submissions for variant NM_001369.3(DNAH5):c.7407+1G>A

dbSNP: rs749711805

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001386279	SCV001586451	pathogenic	Primary ciliary dyskinesia	2022-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1073312). Disruption of this splice site has been observed in individual(s) with DNAH5-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 44 of the DNAH5 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 DNAH5 are known to be pathogenic (PMID: 11788826, 16627867).
GeneDx	RCV002259391	SCV002538710	likely pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV001386279	SCV002671600	likely pathogenic	Primary ciliary dyskinesia	2020-11-19	criteria provided, single submitter	clinical testing	The c.7407+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 44 of the DNAH5 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This variant has been detected in conjunction with a pathogenic mutation in DNAH5 in multiple affected individuals (Ambry internal data). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/251366) total alleles studied. This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003898365	SCV004716797	likely pathogenic	DNAH5-related condition	2023-11-03	criteria provided, single submitter	clinical testing	The DNAH5 c.7407+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-13811755-C-T). Variants that disrupt the consensus splice donor site in DNAH5 are expected to be pathogenic. This variant is interpreted as likely pathogenic.