Variant: NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe)

CA305301758

438325 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: a48735f3-cd3e-4da7-96bf-e0823e89c216

Approved on: 2023-11-07

Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1739C>T
NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe)
NC_000019.10:g.11116892C>T
CM000681.2:g.11116892C>T
NC_000019.9:g.11227568C>T
CM000681.1:g.11227568C>T
NC_000019.8:g.11088568C>T
NG_009060.1:g.32512C>T
ENST00000252444.10:c.1997C>T
ENST00000559340.2:c.1705+680C>T
ENST00000560467.2:c.1619C>T
ENST00000558518.6:c.1739C>T
ENST00000252444.9:c.1993C>T
ENST00000455727.6:c.1235C>T
ENST00000535915.5:c.1616C>T
ENST00000545707.5:c.1358C>T
ENST00000557933.5:c.1739C>T
ENST00000558013.5:c.1739C>T
ENST00000558518.5:c.1739C>T
ENST00000559340.1:c.426+680C>T
NM_000527.4:c.1739C>T
NM_001195798.1:c.1739C>T
NM_001195799.1:c.1616C>T
NM_001195800.1:c.1235C>T
NM_001195803.1:c.1358C>T
NM_001195798.2:c.1739C>T
NM_001195799.2:c.1616C>T
NM_001195800.2:c.1235C>T
NM_001195803.2:c.1358C>T

Likely Pathogenic

• Met criteria codes: PS4_Supporting PS3_Supporting PP1 PP4 PP3 PM2

• Not Met criteria codes: BA1 BP2 BP3 BP4 BS2 BS4 BS3 BS1 PVS1 PM6 PM3 PM1 PM4 PM5 PS2 PS1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant.

Met criteria codes

• PS4_Supporting: Variant meets PM2 and is identified in 3 unrelated index cases (1 case with DLCN criteria>=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases with DLCN criteria>=6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca). So, PS4_Supporting is met.
• PS3_Supporting: Level 3 assay: PMID 35474963: Heterozygous patients monocytes and lymphocytes - results - 25-50% low-density lipoprotein particle uptake and LDLR surface expression. ---- Overall LDLR expression and activity is below 85% of wild-type activity. So, PS3_Supporting is met.
• PP1: variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca (1 family member positive for variant with LDL-C >75th percentile and 1 family member negative for the variant with LDL-C <50th percentile). So, PP1 is met.
• PP4: Variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded.
• PP3: REVEL=0.907. It is above 0.75, so PP3 is met.
• PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met.

Not Met criteria codes

• BA1: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).
• BP2: No data available
• BP3: No in-frame deletion/insertion
• BP4: REVEL=0.907. It is above 0.5
• BS2: No data available
• BS4: variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca (1 family member positive for variant with LDL-C >75th percentile and 1 family member negative for the variant with LDL-C <50th percentile).
• BS3: Level 2 assay: PMID 21865347: Heterozygous patients' Epstein-Barr virus transformed lymphocytes, FACS assays - results - 64% low-density lipoprotein particle receptor activity ---- Overall LDLR activity is below 85% of wild-type activity.
• BS1: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).
• PVS1: Not a null variant
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No data available
• PM1: Not in exon 4, not a cysteine residue
• PM4: No in-frame deletion/insertion
• PM5: 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1738T>C (p.Ser580Pro) (ClinVar ID 375822) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1739C>G (p.Ser580Cys) (ClinVar ID 921461) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No other missense variant in the same codon resulting in a similar amino acid change