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.1463T>C (p.Ile488Thr)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA10585467

251857 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 472302a7-a008-49a5-b31e-c411f07e8e3a

Approved on: 2023-06-23

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1463T>C

NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr)

NC_000019.10:g.11113639T>C

CM000681.2:g.11113639T>C

NC_000019.9:g.11224315T>C

CM000681.1:g.11224315T>C

NC_000019.8:g.11085315T>C

NG_009060.1:g.29259T>C

ENST00000252444.10:c.1721T>C

ENST00000559340.2:c.1463T>C

ENST00000560467.2:c.1343T>C

ENST00000558518.6:c.1463T>C

ENST00000252444.9:c.1717T>C

ENST00000455727.6:c.959T>C

ENST00000535915.5:c.1340T>C

ENST00000545707.5:c.1082T>C

ENST00000557933.5:c.1463T>C

ENST00000558013.5:c.1463T>C

ENST00000558518.5:c.1463T>C

ENST00000559340.1:c.184T>C

NM_000527.4:c.1463T>C

NM_001195798.1:c.1463T>C

NM_001195799.1:c.1340T>C

NM_001195800.1:c.959T>C

NM_001195803.1:c.1082T>C

NM_001195798.2:c.1463T>C

NM_001195799.2:c.1340T>C

NM_001195800.2:c.959T>C

NM_001195803.2:c.1082T>C

Likely Pathogenic

PM2 PS4_Supporting PP1_Moderate PS3_Supporting PP4 PP3

PM3 PM1 PM4 PM5 PM6 PVS1 BA1 BS2 BS4 BS3 BS1 BP7 BP2 BP4 PS2 PS1

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.1463T>C (p.Ile488Thr) name variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP1_Moderate, PS4_Supporting, PS3_Supporting, PP3, 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 v2.1.1). PP3: REVEL = 0.888. PS3_Supporting - Level 3 assay: PMID: 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays - 20-39% LDLR expression and 45-63% LDLR activity ---- results are below 85% of wild-type activity, so PS3_Supporting is met. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 unrelated FH cases (3 index cases with possible FH by Simon Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; 1 index case with definite FH from PMID 11810272 (Fouchier et al., 2001), The Netherlands), after alternative causes of high cholesterol were excluded. PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis from 4 families from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal: 4 affected family members have the variant and 1 non-affected family member does not have the variant.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

PS4_Supporting

Variant meets PM2 and is identified in at least 4 unrelated FH cases (3 index cases with SB criteria of possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, and 1 index case with definite heterozygous FH from the Netherlands, PMID 11810272), after alternative causes of high cholesterol were excluded, so PS4_Supporting is Met.

PP1_Moderate

Variant segregates with FH phenotype in at least 5 informative meiosis from 4 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 4 affected family members have the variant and 1 non-affected family member does not has the variant, so PP1_Moderate is Met.

PS3_Supporting

Level 3 assay: PMID: 37719435: Heterologous cells (CHO), microscopy assays - 20-39% LDLR expression and 45-63% LDLR activity ---- results are below 85% of wild-type activity, so PS3_Supporting is Met.

PP4

Variant meets PM2 and is identified in at least 4 unrelated FH cases (3 index cases with SB criteria of possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, and 1 index case with definite heterozygous FH from the Netherlands), after alternative causes of high cholesterol were excluded, so PP4 is Met.

PP3

REVEL = 0.888. It is above 0.75, so PP3 is Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residue, so PM1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1463T>G (p.Ile488Ser) (ClinVar ID 251858) - VUS by these guidelines - NM_000527.5(LDLR):c.1463T>A (p.Ile488Asn) (ClinVar ID 251856) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PM6

de novo occurrence data not reported, so PS2 is Not Met.

PVS1

Variant is missense, so PVS1 is Not Met.

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.

BS2

Variant is not detected in 104 normolipidemic from the Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, and is identified in only 1 heterozygous non-affected family member from Laboratory of Genetics and Molecular Cardiology, so BS2 is Not Met.

BS4

Variant does not segregate with FH phenotype in 3 informative meiosis 2 families from different labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge and Laboratory of Genetics and Molecular Cardiology): 2 affected family members (LDL-C >75th percentile) do not have the variant and 1 non-affected family member (LDL-C<50th percentile) has the variant, so BS4 in not met.

BS3

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

BP4

REVEL = 0.888. It is not below 0.50, so BP4 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

Curation History

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