ClinVar Miner

Submissions for variant NM_017950.4(CCDC40):c.2712-1G>T (rs370706991)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779234 SCV000915786 likely pathogenic Ciliary dyskinesia, primary, 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.
Invitae RCV000465864 SCV000547201 pathogenic Primary ciliary dyskinesia 2018-10-01 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 and likely results in an absent or disrupted protein product. This variant is present in population databases (rs370706991, ExAC 0.006%). This variant has been reported in several families affected with primary ciliary dyskinesia (PMID: 22693285, 23255504). Two unrelated affected individuals were homozygous for this variant while two other individuals were compound heterozygous with known pathogenic mutations. 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, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.

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