ClinVar Miner

Submissions for variant NM_001271.4(CHD2):c.4173dup (p.Gln1392fs) (rs749969667)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000332337 SCV000329670 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing The c.4173dupA pathogenic variant in the CHD2 gene has been reported previously as a de novo pathogenic variant in two unrelated individuals with epilepsy, one with Lennox-Gastaut syndrome and the second with eyelid myoclonia with absences (Lund et al., 2014; Galizia et al., 2015). The c.4173dupA variant causes a frameshift starting with codon Glutamine 1392, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Gln1392ThrfsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.4173dupA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.4173dupA as a pathogenic variant.
Mendelics RCV000202632 SCV001139724 uncertain significance Epileptic encephalopathy, childhood-onset 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000202632 SCV001219561 pathogenic Epileptic encephalopathy, childhood-onset 2019-02-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1392Thrfs*17) in the CHD2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to be de novo in individuals affected with childhood-onset epileptic encephalopathy (PMID: 24614520) and other photosensitive epileptic syndromes (PMID: 2578359, 26754451). Loss-of-function variants in CHD2 are known to be pathogenic (PMID: 23708187, 24207121). For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001251208 SCV001424581 pathogenic Autistic behavior; Seizures 2020-07-24 criteria provided, single submitter clinical testing Frameshift variant absent from gnomAD v3. Several publications. Sanger confirmed.
GeneReviews RCV000202632 SCV000257590 pathogenic Epileptic encephalopathy, childhood-onset 2015-09-10 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000845032 SCV000986868 not provided CHD2-Related Disorder no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 09/19/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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