The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


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

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 6
PP1_Moderate PP4 PP3 PM2 PS4_Supporting BS3
Not Met criteria codes 16
PS2 PS3 PS1 PM3 PM1 PM4 PM5 PM6 BA1 BS2 BS4 BS1 PVS1 BP2 BP3 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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.
PP3
REVEL=0.898. It is above 0.75, so PP3 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
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).
BS2
No data available.
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).
PVS1
Not a null variant
BP2
No data available.
BP3
No in-frame deletions/insertions.
BP4
REVEL=0.898. It is above 0.5.
Approved on: 2023-04-28
Published on: 2023-04-30
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