Variant: NM_000527.5(LDLR):c.1567G>A (p.Val523Met)

CA023525

3696 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 807ceefc-47d3-4100-bd75-2ef587f3e26b

Approved on: 2023-01-27

Published on: 2024-10-07

HGVS expressions

NM_000527.5:c.1567G>A
NM_000527.5(LDLR):c.1567G>A (p.Val523Met)
NC_000019.10:g.11113743G>A
CM000681.2:g.11113743G>A
NC_000019.9:g.11224419G>A
CM000681.1:g.11224419G>A
NC_000019.8:g.11085419G>A
NG_009060.1:g.29363G>A
ENST00000252444.10:c.1825G>A
ENST00000559340.2:c.1567G>A
ENST00000560467.2:c.1447G>A
ENST00000558518.6:c.1567G>A
ENST00000252444.9:c.1821G>A
ENST00000455727.6:c.1063G>A
ENST00000535915.5:c.1444G>A
ENST00000545707.5:c.1186G>A
ENST00000557933.5:c.1567G>A
ENST00000558013.5:c.1567G>A
ENST00000558518.5:c.1567G>A
ENST00000559340.1:c.288G>A
NM_000527.4:c.1567G>A
NM_001195798.1:c.1567G>A
NM_001195799.1:c.1444G>A
NM_001195800.1:c.1063G>A
NM_001195803.1:c.1186G>A
NM_001195798.2:c.1567G>A
NM_001195799.2:c.1444G>A
NM_001195800.2:c.1063G>A
NM_001195803.2:c.1186G>A

Pathogenic

• Met criteria codes: PP1_Strong PS3_Moderate PP4 PP3 PM3 PS4 PM2

• Not Met criteria codes: BA1 BP5 BP4 BP1 BS4 BS1 PP2 PM5 PM1 PS1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR): c.1567G>A (p.Val523Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PM3, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003266 (0.003%) in East Asian (gnomAD v2.1.1). PP3: REVEL = 0.917. PS3_Moderate: Functional studies: PMID 1301956 (Hobbs et al., 1992), Level 2 assay using homozygous patients' fibroblasts, 125I-LDL assays - 15-30% LDLR activity (but all cycle was tested) // PMID 9974426 (Bertolini et al., 1999), Level 2 assay using homozygous patient fibroblast, 125I-LDL assays - 25% LDLR activity, (mention of testing LDL binding, internalization, and degradation) // PMID 21865347 (Romano et al., 2011), Level 3 assays using heterozygous patients' Epstein-Barr virus transformed lymphocytes and FACS assays - 30-40% LDLR activity. // PMID 25647241 (Thormaehlen et al., 2015), functional studies using HeLa cells and alternative microscopy assay showed that the LDLR activity is decreased compared to WT and was considered as "disruptive" ------ Overall, functional studies (PMID 1301956, 9974426, 21865347) show an activity below 70% of wild-type, consistent with damaging effect and PS3 is met. PS4, PP4: Variant meets PM2 and is identified in at least 22 unrelated cases, 2 fulfilling Simon-Broome criteria (GeneDx) and 20 with DLCN score >=6 (Service de Biochimie et de Biologie Moléculaire, France; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy; Robarts Research Institute, Canada). PP1_Strong: variant segregates with FH phenotype in 14 informative meioses in 8 families from different labs (Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology, Brazil; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine, Italy): 11 affected family members have the variant and 3 non-affected family members do not have the variant. PM3: 1 case reported from Service de Biochimie et de Biologie Moléculaire, France (homozygous and LDL-cholesterol 12 mmol/L at 4 years old).

Met criteria codes

• PP1_Strong: PP1_Strong: variant segregates with FH phenotype in 14 informative meioses in 8 families from different labs (Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology; and, Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine): 11 affected family members have the variant and 3 non-affected family members do not have the variant. So, PP1_Strong is met.
• PS3_Moderate: PS3_Moderate: Functional studies: (PMID: 1301956) Level 2 assay using Homozygous patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) // (PMID: 9974426) Level 2 assay using Homozygous patient fibroblast, 125I-LDL assays - results - 25% LDLR activity, (mention of testing LDL binding, internalization, and degradation) // (PMID: 21865347) Level 3 assays using Heterozygous patients' Epstein-Barr virus transformed lymphocytes and FACS assays - results - 30-40% LDLR activity. // (PMID:25647241) functional studies using HeLa cells and alternative microscopy assay showed that the LDLR activity is decreased compared to WT and was considered as "disruptive" ------ Overall, functional studies (PMID:1301956, 9974426, 21865347) show an activity below 70% of wild-type, so functional study is consistent with damaging effect and PS3 is met.
• PP4: PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills possible/definite FH criteria (DLCN>=6/SB) after alternative causes of high cholesterol were excluded from the Service de Biochimie et de Biologie Moléculaire, France; Laboratory of Genetics and Molecular Cardiology; and, Research Lab of Molecular Genetics of Lipid Metabolism).
• PP3: PP3: REVEL = 0.917. It is above 0.75.
• PM3: PM3: 1 case reported in the VCI (from Service de Biochimie et de Biologie Moléculaire, France) is homozygous and presents LDLc 12 mmol/L at 4 years old.
• PS4: PS4: Variant meets PM2 and is identified in at leat 22 unrelated cases, 2 fulfilling Simon-Broome criteria (GeneDx) and 20 presenting Dutch lipid clinic network >=6 criteria (Service de Biochimie et de Biologie Moléculaire, France; Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca Department of Translational and Precision Medicine; and, Robarts Research Institute). In the relevant evidence column are metioned several PMIDs reporting more individuals).
• PM2: PM2: PopMax MAF = 0.00003266 (0.003%) in East Asian (gnomAD v2.1.1). PM2 is met since PopMax MAF < 0.02%.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: Not applicable
• BP4: REVEL = 0.917. It is not below 0.50.
• BP1: Not applicable
• BS4: No instance of variant non-segregation with FH phenotype in at least 2 informative meiosis from at least 2 families with at least one unaffected relative (LDL-C <50th centile) who is positive for the variant.
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: Not applicable
• PM5: PM5_Not Met : There are 2 missense variants that lead to a different amino acid change (c.1567G>C and c.1567G>T (p.Val523Leu)) but they are not classified as pathogenic by these guidelines.
• PM1: PM1_Not Met : Variant meets PM2 but it is in exon 10.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline