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]
  • Gene label mismatch: LDLR vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data

Variant: NM_000527.5(LDLR):c.1088C>T (p.Thr363Ile)

CA032045

1967129 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: bdb33614-16ee-439c-ad64-b6346526d6a4
Approved on: 2025-03-24
Published on: 2025-03-24

HGVS expressions

NM_000527.5:c.1088C>T
NM_000527.5(LDLR):c.1088C>T (p.Thr363Ile)
NC_000019.10:g.11111541C>T
CM000681.2:g.11111541C>T
NC_000019.9:g.11222217C>T
CM000681.1:g.11222217C>T
NC_000019.8:g.11083217C>T
NG_009060.1:g.27161C>T
ENST00000252444.10:c.1346C>T
ENST00000559340.2:c.1088C>T
ENST00000560467.2:c.968C>T
ENST00000558518.6:c.1088C>T
ENST00000252444.9:c.1342C>T
ENST00000455727.6:c.584C>T
ENST00000535915.5:c.965C>T
ENST00000545707.5:c.707C>T
ENST00000557933.5:c.1088C>T
ENST00000558013.5:c.1088C>T
ENST00000558518.5:c.1088C>T
ENST00000560173.1:n.87C>T
ENST00000560467.1:c.568C>T
NM_000527.4:c.1088C>T
NM_001195798.1:c.1088C>T
NM_001195799.1:c.965C>T
NM_001195800.1:c.584C>T
NM_001195803.1:c.707C>T
NM_001195798.2:c.1088C>T
NM_001195799.2:c.965C>T
NM_001195800.2:c.584C>T
NM_001195803.2:c.707C>T
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Uncertain Significance

Met criteria codes 2
PM2 BP4
Not Met criteria codes 5
PS1 PP3 PM5 BA1 BS1

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1088C>T (p.Thr363Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003334 (0.003334%) in Admixed American exomes+genomes (gnomAD v4.1.0). BP4: REVEL=0.289, it is below 0.5, splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby: First AG -- MES score: variant cryptic site= 3.16, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 3.16/2.69=1.175 --- It is above > 1.1. Ratio Var cryptic/Wt canonical= 3.16/13.90=0.227 --- it is NOT above > 0.9. Second AG -- MES score: variant cryptic site= -2.41, wt cryptic site= -3.45, canonical WT site=13.90. Variant not predicted to alter splicing.
Met criteria codes
PM2
PopMax MAF = 0.00003334 (0.003334%) in Admixed American exomes+genomes (gnomAD v4.1.0).
BP4
REVEL=0.289, it is below 0.5, splicing evaluation required. Functional data on splicing is not available. A) not on limits, B) does not create AG, C) there are two AG nearby: First AG -- MES score: variant cryptic site= 3.16, wt cryptic site= 2.69, canonical WT site=13.90. Ratio Var cryptic/Wt cryptic= 3.16/2.69=1.175 --- It is above > 1.1. Ratio Var cryptic/Wt canonical= 3.16/13.90=0.227 --- it is NOT above > 0.9. Second AG -- MES score: variant cryptic site= -2.41, wt cryptic site= -3.45, canonical WT site=13.90. Variant not predicted to alter splicing.
Not Met criteria codes
PS1
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn) (ClinVar ID 251656) - Conflicting classifications of pathogenicity by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines.
PP3
REVEL=0.289, it is below 0.5. Splicing evaluation required. Functional data on splicing is not available. A) not on limits B) does not create AG C) there are two AG nearby: First AG: variant cryptic site= 3.16, wt cryptic site= 2.69, canonical WT site=13.90 Ratio Var cryptic/Wt cryptic= 3.16/2.69=1.175 => Above 1.1 Ratio Var cryptic/Wt canonical= 3.16/13.90=0.227 => Not above 0.9 Second AG: variant cryptic site= -2.41, wt cryptic site= -3.45, canonical WT site=13.90 Ratio Var cryptic/Wt cryptic= -2.41/-3.45=0.699 => Not above 1.1 Ratio Var cryptic/Wt canonical= -2.41/13.90=-0.173 => Not above 0.9 Variant not predicted to alter splicing.
PM5
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn) (ClinVar ID 251656) - Conflicting classifications of pathogenicity by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines.
BA1
FAF = 0.000005530 (0.0005530%) in Admixed American (gnomAD v4.1.0).
BS1
FAF = 0.000005530 (0.0005530%) in Admixed American (gnomAD v4.1.0).
Curation History
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