Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV001195545 | SCV001365929 | pathogenic | CHARGE association | 2019-06-05 | criteria provided, single submitter | clinical testing | The p.Gln2426SerfsX17 variant in CHD7 has not been previously reported in individuals with CHARGE syndrome and is absent from large population studies. However, this variant was confirmed to be de novo in an individual with moderate developmental delays, bilateral sensorineural hearing loss, retinal coloboma, scoliosis, and vesicoureteral reflux by the Broad Institute Rare Genomes Project. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2426 and is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CHD7 gene is an established disease mechanism in individuals with CHARGE syndrome. In summary, this variant meets criteria to be classified as pathogenic for CHARGE syndrome in an autosomal dominant manner based upon de novo occurrence, its absence from the general population, and its predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PS2, PM2. |
Broad Institute Rare Disease Group, |
RCV001195545 | SCV003922260 | pathogenic | CHARGE association | 2023-05-02 | criteria provided, single submitter | curation | The heterozygous p.Gln2426SerfsTer17 variant in CHD7 was identified by our study in one individual with developmental delay, bilateral sensorineural hearing loss, retinal coloboma, scoliosis, and vesicoureteral reflux (Broad Institute Rare Genomes Project). Trio genome analysis showed this variant to be de novo. The p.Gln2426SerfsTer17 variant in CHD7 has not been previously reported in individuals with CHARGE syndrome. This variant has also been reported in ClinVar (Variation ID: 930111) and has been interpreted as pathogenic by Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2426 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the CHD7 gene is an established disease mechanism in CHARGE syndrome. In summary, this variant meets criteria to be classified as pathogenic for CHARGE syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting (Richards 2015). |