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Background  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.    Methods  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.    Results  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).    Conclusions  The c.344G > A: p.(Arg115His) variant in the  LDLR  gene is interpreted as benign in individuals with FH.

The benign c.344G > A: p.(Arg115His) variant in the LDLR gene interpreted from a pedigree-based genetic analysis of familial hypercholesterolemia