ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminal domain of the MAX protein, which is essential for protein localization to the nucleus and suppression of MYC transactivation activity (PMID: 1459463, 1730412, 7630640). While functional studies have not been performed to directly test the effect of this variant on MAX protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 532511). This frameshift has been observed in individual(s) with pheochromocytoma (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the MAX gene (p.Asn78Thrfs*92). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the MAX protein and extend the protein by 8 additional amino acid residues.

The c.228delG pathogenic mutation, located in coding exon 4 of the MAX gene, results from a deletion of one nucleotide at position 228, causing a translational frameshift with a predicted alternate stop codon (p.N78Tfs*92). This frameshift occurs at the 3' terminus of MAX and is not expected to trigger nonsense-mediated mRNA decay; however this variant alters more than half of the original coding sequence of the gene and results in the elongation of the protein by 8 amino acids. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.225delG pathogenic mutation has been detected in a family meeting clinical criteria for paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.