Through WES (Whole Exome Sequencing) analysis, a mutation was detected in the HMBS gene (exon 10, c.651G>C, p.Gln217His) in the proband. Further validation through Sanger sequencing confirmed the presence of this specific mutation in both the proband’s father and brother (refer to Figure 2 for mutant and wild-type validation results). It is noteworthy that neither the father nor the brother displayed any clinical phenotypes associated with this mutation. Based on the family pedigree depicted in Figure 2, it can be inferred that the variant originated from the proband’s father.
This identified mutation has not been observed in normal population databases such as 1000Genome, MutIn Database, ESP6500, ExAC. Additionally, it has not yet been cataloged in the ClinVar database. The REVEL software assigned a score of 0.979 (>0.75 indicating predicted pathogenicity), while the ClinPred software yielded a score of 0.9998 (>0.5 indicating predicted pathogenicity). MutationTaster assessed a pathogenicity score of 1 (conservative prediction shown in Figure 2). Both SIFT and PolyPhen-2 software predicted deleterious effects on protein function. Tertiary protein structural prediction using the 3EQ1 model successfully revealed alterations in protein structure (Figure 2). Furthermore, this mutation has been previously reported in the Chinese population.
Following guidelines provided by the American College of Medical Genetics and Genomics (ACMG), this variation is considered likely pathogenic
内容由零声教学AI助手提供，问题来源于学员提问
