ClinVar Miner

Submissions for variant NM_017950.4(CCDC40):c.940-2A>G (rs750708201)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000221299 SCV000819180 pathogenic Primary ciliary dyskinesia 2018-02-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 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 (rs750708201, ExAC 0.003%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individual affected with primary ciliary dyskinesia (PMID: 23255504, Invitae database). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 228326). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000221299 SCV000271343 pathogenic Primary ciliary dyskinesia 2015-02-10 criteria provided, single submitter clinical testing The c.940-2A>G variant in CCDC40 has been previously reported in 2 compound hete rozygous individuals with primary ciliary dyskinesia (PCD) who carried pathogeni c CCDC40 variants in trans (Becker-Heck 2011, Antony2013). This variant has been identified in 2/66492 Non-Finnish European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered spl icing leading to an abnormal or absent protein. Functional studies indicate that loss of CCDC40 function results in abnormal cilia structure and motility (Becke r-Heck 2011). In summary, this variant meets our criteria to be classified as pa thogenic for PCD in an autosomal recessive manner (http://www.partners.org/perso nalizedmedicine/LMM) based upon the predicted impact to protein and multiple co- occurrences with other pathogenic variants.

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