ClinVar Miner

Submissions for variant NM_017780.4(CHD7):c.6304G>T (p.Val2102Phe) (rs753559567)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414671 SCV000491697 uncertain significance not specified 2016-11-04 criteria provided, single submitter clinical testing The V2102F variant in the CHD7 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. A missense variant in same residue (V2102I) has been reported in an individual diagnosed with CHARGE syndrome, however parental testing was not performed to determine if the variant was inherited or de novo (Félix et al., 2006). In addition, functional studies of the V2102I variant did not show a disruption defect between CHD7 and CHD8 (Batsukh et al., 2010). The V2102F variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V2102F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V2102F as a variant of uncertain significance.
Invitae RCV000462388 SCV000552232 uncertain significance CHARGE association 2016-11-26 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 2102 of the CHD7 protein (p.Val2102Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs753559567, ExAC 0.003%) but has not been reported in the literature in individuals with a CHD7-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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