Variant: NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)

CA10584797

251081 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 85164e00-b749-4e7b-b39c-dd95d97ecbfe

Approved on: 2023-04-28

Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.226G>T
NM_000527.5(LDLR):c.226G>T (p.Gly76Trp)
NC_000019.10:g.11102699G>T
CM000681.2:g.11102699G>T
NC_000019.9:g.11213375G>T
CM000681.1:g.11213375G>T
NC_000019.8:g.11074375G>T
NG_009060.1:g.18319G>T
ENST00000558518.6:c.226G>T
ENST00000252444.9:n.480G>T
ENST00000455727.6:c.226G>T
ENST00000535915.5:c.190+2354G>T
ENST00000545707.5:c.226G>T
ENST00000557933.5:c.226G>T
ENST00000557958.1:n.312G>T
ENST00000558013.5:c.226G>T
ENST00000558518.5:c.226G>T
NM_000527.4:c.226G>T
NM_001195798.1:c.226G>T
NM_001195799.1:c.190+2354G>T
NM_001195800.1:c.226G>T
NM_001195803.1:c.226G>T
NM_001195798.2:c.226G>T
NM_001195799.2:c.190+2354G>T
NM_001195800.2:c.226G>T
NM_001195803.2:c.226G>T

Uncertain Significance

• Met criteria codes: PP4 PP3 PP1_Moderate PM2 PS4_Supporting BS3

• Not Met criteria codes: PVS1 PS2 PS3 PS1 PM3 PM1 PM4 PM5 PM6 BA1 BS4 BS1 BS2 BP2 BP3 BP4

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.226G>T (p.Gly76Trp) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes BS3, PS4_Supporting, PM2, PP1_Moderate, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BS3: Level 1 assays: PMID 25741862: Heterologous cells (CHO), western blot and flow cytometry assays - result: 100% low-density lipoprotein particle receptor biosynthetic process; 90% low-density lipoprotein particle binding; 95% low-density lipoprotein particle clearance. ---- The whole cycle is above 90% of wild-type activity. So, BS3 is met. PS4_Supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille and 1 case with Simon Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). So, PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.898. It is above 0.75, so PP3 is met. PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. So, PP1_Moderate is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from different labs, after alternative causes of high cholesterol were excluded (see PS4 for details). So, PP4 is met.

Met criteria codes

• PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from different labs, after alternative causes of high cholesterol were excluded (see PS4 for details). So, PP4 is met.
• PP3: REVEL=0.898. It is above 0.75, so PP3 is met.
• PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. So, PP1_Moderate is met.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.
• PS4_Supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille and 1 case with Simon Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). So, PS4_Supporting is met.
• BS3: Level 1 assays: PMID 25741862: Heterologous cells (CHO), western blot and flow cytometry assays - result: 100% low-density lipoprotein particle receptor biosynthetic process; 90% low-density lipoprotein particle binding; 95% low-density lipoprotein particle clearance. ---- The whole cycle is above 90% of wild-type activity. So, BS3 is met.

Not Met criteria codes

• PVS1: Not a null variant
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: Level 1 assays: PMID 25741862: Heterologous cells (CHO), western blot and flow cytometry assays - result: 100% low-density lipoprotein particle receptor biosynthetic process; 90% low-density lipoprotein particle binding; 95% low-density lipoprotein particle clearance. ---- The whole cycle is above 90% of wild-type activity.
• PS1: No other missense variant with the same amino acid change.
• PM3: No data available.
• PM1: Not on exon 4. Not a cysteine residue.
• PM4: No in-frame deletions/insertions.
• PM5: 1 other missense variant in the same codon: NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) (ClinVar ID 251081) Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BS2: No data available.
• BP2: No data available.
• BP3: No in-frame deletions/insertions.
• BP4: REVEL=0.898. It is above 0.5.