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The benign c.344G > A: p.(Arg115His) variant in the LDLR gene interpreted from a pedigree-based genetic analysis of familial hypercholesterolemia
- Source :
- Lipids in Health and Disease, Vol 19, Iss 1, Pp 1-5 (2020), Lipids in Health and Disease
- Publication Year :
- 2020
- Publisher :
- BMC, 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Apolipoprotein B
Endocrinology, Diabetes and Metabolism
Annotation
Clinical Biochemistry
Familial hypercholesterolemia
Short Report
030204 cardiovascular system & hematology
Genetic analysis
Polymorphism, Single Nucleotide
Hyperlipoproteinemia Type II
03 medical and health sciences
Young Adult
0302 clinical medicine
Endocrinology
medicine
Humans
Family
Genetic Predisposition to Disease
Variant
Gene
Allele frequency
lcsh:RC620-627
Genetics
biology
PCSK9
Biochemistry (medical)
nutritional and metabolic diseases
LDL receptor
Middle Aged
medicine.disease
Pedigree
lcsh:Nutritional diseases. Deficiency diseases
030104 developmental biology
Receptors, LDL
Benign
biology.protein
Kexin
Female
lipids (amino acids, peptides, and proteins)
Proprotein Convertase 9
Subjects
Details
- Language :
- English
- Volume :
- 19
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Lipids in Health and Disease
- Accession number :
- edsair.doi.dedup.....9621370bafd29602be542c44726453bf
- Full Text :
- https://doi.org/10.1186/s12944-020-01252-4