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.2324T>C (p.Val775Ala)

CA039797

440691 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 7c83984e-b866-4cfc-b84a-f95a0fe505d9

Approved on: 2025-03-28

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.2324T>C

NM_000527.5(LDLR):c.2324T>C (p.Val775Ala)

NC_000019.10:g.11128020T>C

CM000681.2:g.11128020T>C

NC_000019.9:g.11238696T>C

CM000681.1:g.11238696T>C

NC_000019.8:g.11099696T>C

NG_009060.1:g.43640T>C

ENST00000252444.10:c.2582T>C

ENST00000559340.2:c.*393T>C

ENST00000560467.2:c.2204T>C

ENST00000558518.6:c.2324T>C

ENST00000252444.9:c.2578T>C

ENST00000455727.6:c.1820T>C

ENST00000535915.5:c.2201T>C

ENST00000545707.5:c.1790T>C

ENST00000557933.5:c.2324T>C

ENST00000558013.5:c.2324T>C

ENST00000558518.5:c.2324T>C

ENST00000560628.1:n.108+366T>C

NM_000527.4:c.2324T>C

NM_001195798.1:c.2324T>C

NM_001195799.1:c.2201T>C

NM_001195800.1:c.1820T>C

NM_001195803.1:c.1790T>C

NM_001195798.2:c.2324T>C

NM_001195799.2:c.2201T>C

NM_001195800.2:c.1820T>C

NM_001195803.2:c.1790T>C

Uncertain Significance

PM2 BP4

PM3 PM1 PM4 PM5 PM6 BS4 BS3 BS1 BS2 PVS1 PS2 PS4 PS3 PS1 BP7 BP2 BP3 BA1 PP4 PP1 PP3

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.2324T>C (p.Val775Ala) 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 28 March 2025. The supporting evidence is follows: PM2: PopMax MAF = 0.00002627 (0.0026%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0). BP4: REVEL=0.244. It is below 0.5, so splicing evaluation is required. A) not on limits B) does not create AG C) there is an AG nearby. MES scores: variant cryptic = 1.45, wt cryptic = 2.52, canonical acceptor = 11.36. Ratio variant cryptic/wt cryptic: 0.57 --- it is below 1.1. Ratio variant cryptic/canonical acceptor: 0.12--- it is below 0.9. Variant is not predicted to alter splicing.

PM2

PopMax MAF = 0.00002627 (0.0026%) in European (non-Finnish) exomes+genomes (gnomAD v4.1.0). So, PM2 is met.

BP4

REVEL=0.244. It is below 0.5, so splicing evaluation is required. A) not on limits B) does not create AG C) there is a AG nearby. MES scores: variant cryptic = 1.45, wt cryptic = 2.52, canonical acceptor = 11.36. Ratio variant cryptic/wt cryptic: 0.57 --- it is below 1.1 Ratio variant cryptic/canonical acceptor: 0.12--- it is below 0.9 Variant is not predicted to alter splicing. So, BP4 is met.

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.2323G>A (p.Val775Ile) (ClinVar ID 630377) - 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

BS4

No data available.

BS3

No data available.

BS1

FAF = 0.00001663 (0.0016%) in European (non-Finnish) exomes+genomes (gnomAD v2.4.0).

BS2

No data available.

PVS1

Not a null variant

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

No data available.

PS3

No data available.

PS1

No other missense variant with the same amino acid change.

BP7

Not a synonymous variant

BP2

No data available.

BP3

No in-frame deletions/insertions.

BA1

FAF = 0.00001663 (0.0016%) in European (non-Finnish) exomes+genomes (gnomAD v2.4.0).

PP4

No data available.

PP1

No data available.

PP3

REVEL=0.244. It is below 0.75, so splicing evaluation is required. A) not on limits B) does not create AG C) there is a AG nearby. MES scores: variant cryptic = 1.45, wt cryptic = 2.52, canonical acceptor = 11.36. Ratio variant cryptic/wt cryptic: 0.57 --- it is below 1.1 Ratio variant cryptic/canonical acceptor: 0.12--- it is below 0.9

Curation History

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