Through the utilization of Whole Exome Sequencing (WES) analysis, a mutation in the HMBS gene was detected within exon 10 (c.651G>C, p.Gln217His) of the proband’s genomic sequence. Subsequent Sanger sequencing confirmed the presence of this specific mutation in both the proband’s father and brother, as demonstrated by Figure 2 which showcases validation results comparing mutant and wild-type genotypes. It is worth noting that neither the father nor the brother exhibited any clinical manifestations associated with this mutation, suggesting an asymptomatic carrier state. Based on genetic inheritance patterns depicted in the family pedigree (Figure 2), it is hypothesized that this variant originated from the proband’s father.
Importantly, this identified mutation has not been documented within public databases containing information from normal population cohorts such as 1000Genome, MutIn Database, ESP6500, and ExAC. Furthermore, its absence from the ClinVar database indicates that it has yet to be categorized or evaluated for clinical significance.
Bioinformatic analysis utilizing REVEL software assigned a score of 0.979 to this variant, surpassing the threshold value of 0.75 commonly used to predict pathogenicity. Additionally, ClinPred software yielded a score of 0.9998, further reinforcing its potential pathogenic nature based on a cut-off value greater than 0.5.
MutationTaster prediction classifies this variant as disease-causing (score=1) with notable conservation properties (as depicted in Figure 2). Consistent with these predictions are protein function assessments conducted using SIFT and PolyPhen-2 software, both of which indicate a high likelihood of pathogenicity associated with this alteration.
To gain insights into structural implications, computational modeling utilizing the 3EQ1 protein structure model (accessible at https://www.rcsb.org/structure/3EQ1) was performed successfully, revealing discernible changes in protein structure attributable to this mutation (as illustrated in Figure 2).
Notably, reports regarding the relevance of this specific mutation within the Chinese population have also been documented. In accordance with the guidelines provided by the American College of Medical Genetics and Genomics (ACMG), this variant is considered likely pathogenic based on available evidence and relevant criteria.
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