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>A (p.Ile488Asn)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585466

251856 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5e75692c-3c39-4f57-a4d7-31e4981e73d2

Approved on: 2023-06-23

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1463T>A

NM_000527.5(LDLR):c.1463T>A (p.Ile488Asn)

NC_000019.10:g.11113639T>A

CM000681.2:g.11113639T>A

NC_000019.9:g.11224315T>A

CM000681.1:g.11224315T>A

NC_000019.8:g.11085315T>A

NG_009060.1:g.29259T>A

ENST00000252444.10:c.1721T>A

ENST00000559340.2:c.1463T>A

ENST00000560467.2:c.1343T>A

ENST00000558518.6:c.1463T>A

ENST00000252444.9:c.1717T>A

ENST00000455727.6:c.959T>A

ENST00000535915.5:c.1340T>A

ENST00000545707.5:c.1082T>A

ENST00000557933.5:c.1463T>A

ENST00000558013.5:c.1463T>A

ENST00000558518.5:c.1463T>A

ENST00000559340.1:c.184T>A

NM_000527.4:c.1463T>A

NM_001195798.1:c.1463T>A

NM_001195799.1:c.1340T>A

NM_001195800.1:c.959T>A

NM_001195803.1:c.1082T>A

NM_001195798.2:c.1463T>A

NM_001195799.2:c.1340T>A

NM_001195800.2:c.959T>A

NM_001195803.2:c.1082T>A

Likely Pathogenic

PM2 PS4_Supporting PP3 PP1 PP4

PVS1 BA1 PM6 PM3 PM1 PM4 PM5 BS4 BS3 BS1 BS2 BP7 BP4 BP2 PS1 PS2 PS3

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>A (p.Ile488Asn) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting, PP1, PP3 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 v2.1.1). PP3: REVEL = 0.84. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 unrelated FH index cases (2 cases meeting Simon-Broome criteria from PMID 11668640 (García-García et al., 2001), Spain; 1 case meeting Simon-Broome criteria from PMID 10978268 (Bertolini et al., 2000), Italy; at least 1 case with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583834.1)). PP1: Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from PMID 10978268 (Bertolini et al., 2000), Italy: 2 affected family members 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 index cases: 2 cases with Simon-Broome criteria from Spain (PMID: 11668640), 1 index case with Simon-Broome of possible/definite FH from Italy (PMID: 11668640) and at last 1 case with DLCN criteria of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583834.1), after alternative causes of high cholesterol were excluded, so PS4_Supporting is Met.

PP3

REVEL = 0.84. It is above 0.75, so PP3 is Met.

PP1

Variant segregates with FH phenotype in at least 2 informative meiosis from 1 family from Italy (PMID: 10978268): 2 affected family members have the variant, so PP1 is Met.

PP4

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.

PM6

de novo occurrence data not reported, so PM6 is Not 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>C (p.Ile488Thr) (ClinVar ID 251857) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1463T>G (p.Ile488Ser) (ClinVar ID 251858) - VUS by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

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

BS2

Case-control data not reported, so BS2 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP4

REVEL = 0.84. It is not below 0.50, so BP4 is Not Met.

BP2

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

PS1

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

PS2

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

PS3

There are no functional studies reported for this variant, so PS3 is not met.

Curation History

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