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>G (p.Ile488Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585468

251858 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 1149b986-2c29-48b7-89e4-5188e29d9620

Approved on: 2023-06-23

Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1463T>G

NM_000527.5(LDLR):c.1463T>G (p.Ile488Ser)

NC_000019.10:g.11113639T>G

CM000681.2:g.11113639T>G

NC_000019.9:g.11224315T>G

CM000681.1:g.11224315T>G

NC_000019.8:g.11085315T>G

NG_009060.1:g.29259T>G

ENST00000252444.10:c.1721T>G

ENST00000559340.2:c.1463T>G

ENST00000560467.2:c.1343T>G

ENST00000558518.6:c.1463T>G

ENST00000252444.9:c.1717T>G

ENST00000455727.6:c.959T>G

ENST00000535915.5:c.1340T>G

ENST00000545707.5:c.1082T>G

ENST00000557933.5:c.1463T>G

ENST00000558013.5:c.1463T>G

ENST00000558518.5:c.1463T>G

ENST00000559340.1:c.184T>G

NM_000527.4:c.1463T>G

NM_001195798.1:c.1463T>G

NM_001195799.1:c.1340T>G

NM_001195800.1:c.959T>G

NM_001195803.1:c.1082T>G

NM_001195798.2:c.1463T>G

NM_001195799.2:c.1340T>G

NM_001195800.2:c.959T>G

NM_001195803.2:c.1082T>G

Uncertain Significance

PP3 PP4 PM2

BP4 BP2 BP7 PS1 PS2 PS4 PS3 PVS1 PP1 PM4 PM3 PM1 PM5 PM6 BA1 BS2 BS4 BS3 BS1

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>G (p.Ile488Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, 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 = 0.905. PP4: Variant meets PM2 and is identified in at least 1 FH index case with definite FH by Simon Broome criteria from PMID 20236128 (Taylor et al., 2010), UK, after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.905. It is above 0.75, so PP3 is Met.

PP4

Variant meets PM2 and is identified in at least 1 FH index case with SB criteria of definite FH from UK (PMID: 20236128), after alternative causes of high cholesterol were excluded, so PP4 is Met.

PM2

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

BP4

REVEL = 0.905. 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.

BP7

Variant is not synonymous, so BP7 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.

PS4

Variant meets PM2 and is identified in only index case with SB criteria of definite FH from UK (PMID: 20236128), after alternative causes of high cholesterol were excluded, so PS4 is not met.

PS3

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

PVS1

Variant is missense, so PVS1 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 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.

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>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 PM6 is Not Met.

BA1

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

BS2

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

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.

Curation History

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