ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.3881T>C (p.Leu1294Pro) (rs864309609)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000203151 SCV000258120 likely pathogenic not provided 2015-06-23 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000258103 SCV000328336 pathogenic CHARGE association 2016-09-05 criteria provided, single submitter clinical testing
Invitae RCV000258103 SCV001380790 likely pathogenic CHARGE association 2019-07-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1294 of the CHD7 protein (p.Leu1294Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CHARGE syndrome (PMID: 16400610, 26590800). In at least one individual the variant has been observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 218745). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000258103 SCV001445906 pathogenic CHARGE association 2019-07-31 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with CHARGE Syndrome, in some cases confirmed as present in the de novo state (PMID: 21158681, 22539353, 24979395, 29191495). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.3881T>C (p.Leu1294Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.3881T>C (p.Leu1294Pro) variant is classified as Pathogenic.

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