ClinVar Miner

Submissions for variant NM_016356.5(DCDC2):c.123_124del (p.Ser42fs)

dbSNP: rs757704417
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001335811 SCV001529049 pathogenic Dyslexia, susceptibility to, 2 2018-09-20 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics RCV002498782 SCV002811076 pathogenic Autosomal recessive nonsyndromic hearing loss 66; Nephronophthisis 19; Isolated neonatal sclerosing cholangitis 2024-04-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002515058 SCV003281254 pathogenic Autosomal recessive nonsyndromic hearing loss 66; Isolated neonatal sclerosing cholangitis 2022-04-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser42Glnfs*72) in the DCDC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCDC2 are known to be pathogenic (PMID: 27319779, 27469900). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180688). This premature translational stop signal has been observed in individual(s) with DCDC2-related conditions (PMID: 25557784, 27469900). This variant is present in population databases (rs757704417, gnomAD 0.003%).
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV000477717 SCV005397769 pathogenic Isolated neonatal sclerosing cholangitis 2024-03-14 criteria provided, single submitter clinical testing This sequence variant is a 2 nucleotide deletion (delGT) in the exon 1 of 10 of the DCDC2 gene that results in an early termination codon 72 amino acids downstream of the frameshift at codon 42. This variant is predicted to generate a non-functional allele through either the expression of a truncated protein or a loss of doublecortin domain containing 2 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 180688) that has been observed in both homozygous and compound heterozygous states in individuals affected by hepatic ciliopathy and neonatal sclerosing cholangitis (PMID: 25557784, 37296768, 27469900, 36938759). This variant is present in 5 of 400306 alleles (0.0012%) in the gnomAD population dataset. Functional studies have found that the protein resulting from this variant failed to properly localize in the primary cilium, did not interact with its protein partners, and could not rescue mouse kidney cells in which DCDC2 expression was knocked-down (PMID: 25557784). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PS3, PVS1
OMIM RCV000157643 SCV000207600 pathogenic Nephronophthisis 19 2015-01-08 no assertion criteria provided literature only
OMIM RCV000477717 SCV000564216 pathogenic Isolated neonatal sclerosing cholangitis 2015-01-08 no assertion criteria provided literature only

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