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KMID : 1100820220120020116
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Laboratory Medicine Online
2022 Volume.12 No. 2 p.116 ~ p.121
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Re-evaluation of the LDLR Gene Variants of Uncertain Significance Using ClinGen Guideline
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Ha Chang-Hee
Lee Hyun-Seung
Park Hyung-Doo
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Abstract
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Familial hypercholesterolemia (FH) is characterized by elevated LDL cholesterol levels, which is an important risk factor for early-onset cardiovascular disease. FH is one of the common genetic diseases that have a prevalence of approximately 1:250 and is associated with the heterozygous pathogenic variant of the gene encoding for the low-density lipoprotein receptor, LDLR gene (~90%). Variants identified through sequencing analysis are classified according to the American College of Medical Genetics and Association for Molecular Pathology Guideline. However, disease-specific variant curation is performed by the Clinical Genome Resource (ClinGen) Expert Panels. Since a specific ClinGen guideline for FH was recently published, here, we applied this new guideline to re-evaluate and re-classify what was reported as a Variant of Uncertain Significance (VUS) in the LDLR gene. Among 66 different types of LDLR variants from 251 patients during 2011 and 2021, 13 different VUSs reported from 15 patients were re-classified. Among 13 VUSs, two missense variants; c.268G>T (p.D90Y) and c.694G>T (p.A232S), were re-classified to likely pathogenic variants. Using the ClinGen guideline, VUSs previously lacking sufficient evidence to be classified as likely pathogenic have now been appropriately classified. Considering the genetic causes and prevalence of FH, the evaluation and classification of the LDLR gene variants should be updated according to the new ClinGen guideline specific for FH.
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KEYWORD
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Clinical Genome Resource, Familial hypercholesterolemia, Guideline, LDLR, Variant of uncertain significance
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