Evidence Repository - Clinical Genome Resources

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.1189T>A (p.Ser397Thr)

CA10585349

251725 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 77844244-7a2f-49a5-927d-e7b9cfb90aad

Approved on: 2023-06-23

Published on: 2025-09-16

HGVS expressions

NM_000527.5(LDLR):c.1189T>A (p.Ser397Thr)

NM_000527.5:c.1189T>A

NC_000019.10:g.11113280T>A

CM000681.2:g.11113280T>A

NC_000019.9:g.11223956T>A

CM000681.1:g.11223956T>A

NC_000019.8:g.11084956T>A

NG_009060.1:g.28900T>A

ENST00000252444.10:c.1447T>A

ENST00000559340.2:c.1189T>A

ENST00000560467.2:c.1069T>A

ENST00000558518.6:c.1189T>A

ENST00000252444.9:c.1443T>A

ENST00000455727.6:c.685T>A

ENST00000535915.5:c.1066T>A

ENST00000545707.5:c.808T>A

ENST00000557933.5:c.1189T>A

ENST00000558013.5:c.1189T>A

ENST00000558518.5:c.1189T>A

ENST00000560173.1:n.188T>A

ENST00000560467.1:c.669T>A

NM_000527.4:c.1189T>A

NM_001195798.1:c.1189T>A

NM_001195799.1:c.1066T>A

NM_001195800.1:c.685T>A

NM_001195803.1:c.808T>A

NM_001195798.2:c.1189T>A

NM_001195799.2:c.1066T>A

NM_001195800.2:c.685T>A

NM_001195803.2:c.808T>A

Uncertain Significance

PP4 PM2

PS1 BA1 PP3 PM5 BS1 BP4

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1189T>A (p.Ser397Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v20210610). PP4: Variant meets PM2 and is identified in at least 1 index case with clinical Dutch Lipid Clinic Network Criteria score ≥ 6 in PMID 11810272 (Fouchier et al., 2001), The Netherlands, after alternative causes of high cholesterol were excluded.

PP4

Variant meet PM2. PMID: 11810272 (Fouchier SW et al., 2001) in at least 1 patient that was clinically diagnosed with definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria.

PM2

This variant is absent from gnomAD (gnomAD v20210610).

PS1

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1189T>C (p.Ser397Pro) (ClinVar ID 923326) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1190C>T (p.Ser397Phe) (ClinVar ID 925475) - Uncertain significance by these guidelines by these guidelines There are no variant in the same codon classified as Pathogenic by these guidelines.

BA1

This variant is absent from gnomAD (gnomAD v20210610).

PP3

REVEL = 0.504. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) Variant within limits. MES scores: Canonical site variant = 7.03; canonical acceptor wt = 6.59. Ratio: 7.03/6.59 = 1.06---- It is not <0.8. Variant is not predicted to alter splicing.

PM5

BS1

This variant is absent from gnomAD (gnomAD v20210610).

BP4

REVEL = 0.504. It is not below 0.5, splicing evaluation needed. Functional data on splicing not available. A) Variant within limits. MES scores: Canonical site variant = 7.03; canonical acceptor wt = 6.59. Ratio: 7.03/6.59 = 1.06---- It is > 1.0

Curation History

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