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.1394A>G (p.Tyr465Cys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585437

251826 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 546c9d42-68e4-461c-91b8-022bfbb0a61e

Approved on: 2022-10-28

Published on: 2025-02-07

HGVS expressions

NM_000527.5:c.1394A>G

NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys)

NC_000019.10:g.11113570A>G

CM000681.2:g.11113570A>G

NC_000019.9:g.11224246A>G

CM000681.1:g.11224246A>G

NC_000019.8:g.11085246A>G

NG_009060.1:g.29190A>G

ENST00000252444.10:c.1652A>G

ENST00000559340.2:c.1394A>G

ENST00000560467.2:c.1274A>G

ENST00000558518.6:c.1394A>G

ENST00000252444.9:c.1648A>G

ENST00000455727.6:c.890A>G

ENST00000535915.5:c.1271A>G

ENST00000545707.5:c.1013A>G

ENST00000557933.5:c.1394A>G

ENST00000558013.5:c.1394A>G

ENST00000558518.5:c.1394A>G

ENST00000559340.1:c.115A>G

ENST00000560467.1:c.874A>G

NM_000527.4:c.1394A>G

NM_001195798.1:c.1394A>G

NM_001195799.1:c.1271A>G

NM_001195800.1:c.890A>G

NM_001195803.1:c.1013A>G

NM_001195798.2:c.1394A>G

NM_001195799.2:c.1271A>G

NM_001195800.2:c.890A>G

NM_001195803.2:c.1013A>G

Uncertain Significance

PP4 PP3 PM2

BS1 BP7 BP3 BP4 BP1 PVS1 PS4 PS1 BA1 PP1 PP2 PM4 PM5

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.1394A>G (p.Tyr465Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP 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 28 October 2022. The supporting evidence is as follows: PM2: Variant is absent from gnomAD v2.1.1. PP3: REVEL = 0.77. PP4: Variant meets PM2 and is identified in 1 case with definite FH by Simon Broome criteria from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic.

PP4

Variant meets PM2, identified in 1 FH case with Simon Broome critieria definite for FH from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)

PP3

REVEL = 0.77

PM2

Variant is absent from gnomAD v2.1.1

BS1

Variant is absent from gnomAD v2.1.1

BP7

missense

BP3

BP4

REVEL = 0.77

BP1

PVS1

missense

PS4

Only 1 index case meeting FH clinical criteria identified

PS1

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn) (ClinVar ID 252194) - VUS by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines

BA1

Variant is absent from gnomAD v2.1.1

PP1

Variant segregates with FH phenotype in at least 2 informative meiosis from 2 families from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), but neither has an affected relative that carries the variant and the phenotype

PP2

PM4

missense

PM5

Curation History

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