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

Variant: NM_000527.5(LDLR):c.1238C>T (p.Thr413Met)

CA023439

161276 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: d0043f81-8599-437b-b1fc-84609ee67f9a

HGVS expressions

NM_000527.5:c.1238C>T
NM_000527.5(LDLR):c.1238C>T (p.Thr413Met)
ENST00000558518.6:c.1238C>T
ENST00000252444.9:n.1492C>T
ENST00000455727.6:c.734C>T
ENST00000535915.5:c.1115C>T
ENST00000545707.5:c.857C>T
ENST00000557933.5:c.1238C>T
ENST00000558013.5:c.1238C>T
ENST00000558518.5:c.1238C>T
ENST00000560173.1:n.237C>T
ENST00000560467.1:n.718C>T
NM_000527.4:c.1238C>T
NM_001195798.1:c.1238C>T
NM_001195799.1:c.1115C>T
NM_001195800.1:c.734C>T
NM_001195803.1:c.857C>T
NM_001195798.2:c.1238C>T
NM_001195799.2:c.1115C>T
NM_001195800.2:c.734C>T
NM_001195803.2:c.857C>T
NC_000019.10:g.11113329C>T
CM000681.2:g.11113329C>T
NC_000019.9:g.11224005C>T
CM000681.1:g.11224005C>T
NC_000019.8:g.11085005C>T
NG_009060.1:g.28949C>T

Likely Pathogenic

Met criteria codes 4
PS4_Moderate PP4 PP1 PM2
Not Met criteria codes 22
PVS1 BA1 BP2 BP3 BP4 BP1 BP5 BP7 BS2 BS4 BS3 BS1 PP3 PP2 PS2 PS3 PS1 PM3 PM1 PM4 PM5 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.1238C>T (p.Thr413Met) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Moderate, PP1 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 6 index cases. PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory. PP4 - Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria).
Met criteria codes
PS4_Moderate
Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria).
PP4
Variant meets PM2. Variant identified in 6 index cases (2 cases from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with DLCN criteria, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria).
PP1
Variant segregates with phenotype in 2 members of family (2 meiosis) from GeneDx laboratory.
PM2
PopMax MAF = 0.00006533 (0.007%) in South Asian (gnomAD v2.1.1). MAF is below 0.02%.
Not Met criteria codes
PVS1
Missense variant. Not applicable.
BA1
FAF = 0.00001688% (0.001688%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
REVEL: 0,692. Score is not below 0,15.
BP1
Not applicable.
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BS2
No unaffected individuals identified with the variant.
BS4
No variant negative family members were tested.
BS3
Level 1 assay - PMID: 32015373 - Heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (100%) cell surface LDLR, LDL-LDLR binding (80%) and uptake (90%). Binding is below 90%. BS3 not met.
BS1
FAF = 0.00001688% (0.001688%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%
PP3
REVEL: 0,692. Score is not above 0,75. Splicing predictors - negative.
PP2
Not applicable.
PS2
No de novo cases were identified.
PS3
Level 1 assay - PMID: 32015373 - Heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (100%) cell surface LDLR, LDL-LDLR binding (80%) and uptake (90%). Variant results are not below 70% of WT activity in either expression/biosynthesis, binding or internalization. PS3 is not met.
PS1
No variant described that leads to the same amino acid change.
PM3
Not identified in individuals with other variants.
PM1
Missense at codon 413. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM4
Missense variant. Not applicable.
PM5
No other missense variants for this codon in ClinVar database.
PM6
No de novo cases were identified.
Approved on: 2021-06-09
Published on: 2021-06-24
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