We previously identified the c.344G > A: p.(Arg115His) variant in the low-density lipoprotein receptor (LDLR) gene, which was interpreted as “conflicting interpretations of pathogenicity” in ClinVar, based on a genetic analysis of patients with familial hypercholesterolemia (FH). However, whether this variant affects the pathophysiology of FH remains unclear. Therefore, our aim was to annotate the c.344G > A: p.(Arg115His) variant in the LDLR gene in FH. We present 2 families harboring the c.344G > A: p.(Arg115His) variant in the LDLR gene. Genetic analyses were performed for the coding regions and the exon-intron boundary sequence of the LDLR and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes in 2 FH families. Next, the family without pathogenic variants in the LDLR and PCSK9 genes was screened by whole-exome sequencing. Detailed clinical and biochemical data were gathered from family members. In one family, the index case had biallelic c.1567G > A: p.(Val523Met) and c.344G > A: p.(Arg115His) variants in the LDLR gene, while the sibling had only the c.1567G > A: p.(Val523Met) variant in the LDLR gene. There was no difference in the FH phenotype between the siblings. In another family, the index case and the sibling had no pathogenic variants in the LDLR, PCSK9, and apolipoprotein B (APOB) genes, but the sibling’s wife with nonFH had the c.344G > A: p.(Arg115His) variant in the LDLR gene. The sibling and his wife had 4 children, including an unaffected child and an affected child who had the c.344G > A: p.(Arg115His) variant in the LDLR gene. In addition, the allele frequency of the c.344G > A: p.(Arg115His) variant (0.0023–0.0043) in Japanese and East Asian populations is relatively high compared with that of the other LDLR pathogenic variants (0.0001–0.0008). The c.344G > A: p.(Arg115His) variant in the LDLR gene is interpreted as benign in individuals with FH.

中文翻译：

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LDLR基因中的良性c.344G> A：p。（Arg115His）变异来自家族性高胆固醇血症的基于血统的遗传分析

我们先前根据家族性患者的基因分析，确定了低密度脂蛋白受体（LDLR）基因中的c.344G> A：p。（Arg115His）变异体，该变异体在ClinVar中被解释为“致病性冲突解释”高胆固醇血症（FH）。但是，该变体是否影响FH的病理生理尚不清楚。因此，我们的目的是注释FH的LDLR基因中的c.344G> A：p。（Arg115His）变异。我们介绍了2个家族，它们在LDLR基因中具有c.344G> A：p。（Arg115His）变异。对2个FH家族的LDLR和前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）基因的编码区和外显子-内含子边界序列进行了遗传分析。接下来，通过全外显子组测序筛选了LDLR和PCSK9基因中无致病性变异的家族。从家庭成员那里收集了详细的临床和生化数据。在一个家族中，该索引病例在LDLR基因中具有双等位基因c.1567G> A：p。（Val523Met）和c.344G> A：p。（Arg115His）变异，而同胞只有c.1567G> A： LDLR基因中的p。（Val523Met）变体。兄弟姐妹之间的FH表型没​​有差异。在另一个家庭中，索引病例和兄弟姐妹在LDLR，PCSK9和载脂蛋白B（APOB）基因中没有致病性变异，但具有非FH的兄弟姐妹的妻子在其中的c.344G> A：p。（Arg115His）变异LDLR基因。兄弟姐妹和他的妻子有4个孩子，包括一个未受影响的孩子和一个受影响的孩子，他们的LDLR基因具有c.344G> A：p。（Arg115His）变异。另外，c.344G> A的等位基因频率：p。（Arg115His）变异（0.0023-0。与其他LDLR致病变异相比（0.0001-0.0008），日本和东亚人群中的0043）相对较高。LDLR基因中的c.344G> A：p。（Arg115His）变异体在FH患者中被解释为良性。