Submissions for variant NM_017950.4(CCDC40):c.2712-1G>T

dbSNP: rs370706991

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000465864	SCV000547201	pathogenic	Primary ciliary dyskinesia	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 16 of the CCDC40 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 CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). This variant is present in population databases (rs370706991, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 22693285, 23255504). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 407769). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000779234	SCV000915786	likely pathogenic	Primary ciliary dyskinesia 15	2018-10-19	criteria provided, single submitter	clinical testing	The CCDC40 c.2712-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.2712-1G>T variant has been reported in two studies and is found in a total of five patients with inner dynein arm defects including three in a homozygous state and two in a compound heterozygous state (Antony et al. 2013; Blanchon et al. 2012). Two of the homozygotes are siblings (Antony et al. 2013). The variant is also found in four unaffected individuals in a heterozygous state (Antony et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, including the potential impact of splice acceptor variants, the c.2712-1G>T 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223847	SCV002502605	pathogenic	not provided	2022-03-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000465864	SCV002741000	pathogenic	Primary ciliary dyskinesia	2018-03-16	criteria provided, single submitter	clinical testing	The c.2712-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 17 of the CCDC40 gene. This mutation was identified in two compound heterozygous and two homozygous individuals with primary ciliary dyskinesia (Blanchon S et al. J. Med. Genet., 2012 Jun;49:410-6; Antony D et al. Hum. Mutat., 2013 Mar;34:462-72). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000779234	SCV002786406	likely pathogenic	Primary ciliary dyskinesia 15	2022-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003902644	SCV004727462	pathogenic	CCDC40-related condition	2023-11-21	criteria provided, single submitter	clinical testing	The CCDC40 c.2712-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is documented causative for primary ciliary dyskinesia (PCD) (Blanchon et al. 2012. PubMed ID: 22693285). Biallelic pathogenic variants in CCDC40 are known to cause defects in inner dynein arm (IDA) assembly, as well as generalized axonemal disorganization (Becker-Heck et al. 2011. PubMed ID: 21131974; Antony et al. 2011. PubMed ID: 23255504). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78063562-G-T). Variants that disrupt the consensus splice acceptor site in CCDC40 are expected to be pathogenic. This variant is interpreted as pathogenic.