By employing WES (Whole Exome Sequencing) analysis, a notable mutation was ascertained within the HMBS gene (specifically in exon 10, c.651G>C, p.Gln217His) in the proband under investigation. To validate this finding, subsequent Sanger sequencing was conducted and confirmed the presence of this particular mutation in both the proband’s father and brother (for detailed mutant and wild-type validation results, kindly refer to Figure 2). Importantly, neither the father nor the brother displayed any clinical phenotypes that could be attributed to this mutation. Based on the family pedigree depicted in Figure 2, it can be postulated that this variant originated from the proband’s father.
This identified mutation has not been documented within normal population databases such as 1000Genome, MutIn Database, ESP6500, ExAC. Furthermore, it has not yet been cataloged within the ClinVar database. In terms of predictive pathogenicity scores obtained from computational tools employed for assessment purposes: 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 (as illustrated conservatively in Figure 2). Both SIFT and PolyPhen-2 software predicted deleterious effects on protein function consequent to this mutation. Employing the tertiary protein structural prediction model known as 3EQ1 successfully revealed discernible alterations within protein structure (see Figure 2). Moreover, it is noteworthy to mention that this specific mutation has been previously reported among individuals within the Chinese population.
Adhering to guidelines set forth by the American College of Medical Genetics and Genomics (ACMG), this variation is deemed likely pathogenic based on comprehensive assessment criteria applied in this study.
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