Using Whole Exome Sequencing (WES) analysis, a mutation was detected in the HMBS gene at exon 10 (c.651G>C, p.Gln217His) in the proband. Sanger sequencing confirmed the presence of this mutation in both the proband’s father and brother, as shown in Figure 2 with validation results for mutant and wild-type genotypes. Notably, neither the father nor the brother exhibited any clinical phenotypes associated with this mutation. Based on the family pedigree illustrated in Figure 2, it is hypothesized that the variant originated from the proband’s father.
This identified mutation has not been documented in normal population databases such as 1000Genome, MutIn Database, ESP6500, and ExAC. Furthermore, it is not yet cataloged in the ClinVar database indicating its novelty and lack of comprehensive evaluation for clinical significance.
Bioinformatic tools were employed to assess pathogenicity prediction scores for this variant. The REVEL software assigned a score of 0.979 (>0.75 indicates predicted pathogenicity), while the ClinPred software yielded a score of 0.9998 (>0.5 indicates predicted pathogenicity). MutationTaster predicted that this variant is disease-causing with a conservative score of 1 (as depicted in Figure 2). Additionally, both SIFT and PolyPhen-2 software indicated pathogenicity based on protein function prediction.
To gain insights into potential structural alterations caused by this mutation, computational modeling utilizing the 3EQ1 protein structure model (accessible at https://www.rcsb.org/structure/3EQ1) was successfully performed. This revealed discernible changes in protein structure associated with the identified mutation (as demonstrated in Figure 2).
Moreover, reports highlighting the relevance of this specific mutation within the Chinese population have also been documented. In accordance with 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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