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.1747C>G (p.His583Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023564

183124 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8e9e2ceb-e493-4190-93bf-def265f1ee65

Approved on: 2023-11-07

Published on: 2024-12-24

HGVS expressions

NM_000527.5:c.1747C>G

NM_000527.5(LDLR):c.1747C>G (p.His583Asp)

NC_000019.10:g.11116900C>G

CM000681.2:g.11116900C>G

NC_000019.9:g.11227576C>G

CM000681.1:g.11227576C>G

NC_000019.8:g.11088576C>G

NG_009060.1:g.32520C>G

ENST00000252444.10:c.2005C>G

ENST00000559340.2:c.1705+688C>G

ENST00000560467.2:c.1627C>G

ENST00000558518.6:c.1747C>G

ENST00000252444.9:c.2001C>G

ENST00000455727.6:c.1243C>G

ENST00000535915.5:c.1624C>G

ENST00000545707.5:c.1366C>G

ENST00000557933.5:c.1747C>G

ENST00000558013.5:c.1747C>G

ENST00000558518.5:c.1747C>G

ENST00000559340.1:c.426+688C>G

NM_000527.4:c.1747C>G

NM_001195798.1:c.1747C>G

NM_001195799.1:c.1624C>G

NM_001195800.1:c.1243C>G

NM_001195803.1:c.1366C>G

NM_001195798.2:c.1747C>G

NM_001195799.2:c.1624C>G

NM_001195800.2:c.1243C>G

NM_001195803.2:c.1366C>G

Likely Pathogenic

PP3 PM5 PM2 PS3_Supporting

BA1 PS2 PS1 PS4 PP1 PP4 PP2 PVS1 PM3 PM4 PM1 PM6 BS2 BS4 BS1 BS3 BP2 BP3 BP4 BP1 BP7 BP5

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

NM_000527.5(LDLR):c.1747C>G (p.His583Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.000008790 (0.0008790%) in European (non-Finnish) (gnomAD v2.1.1). PP3: REVEL = 0.798. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921). PS3_Supporting: Functional studies (PMID 25647241, Thormaehlen et al., 2015) using HeLa-Kyoto cells, LDLR-GFP construct, WB and CLSM assays - results - most of mutant LDLR is in ER, LDLR activity decreased compared to WT - considered as disruptive. Therefore, PS3_Supporting is met.

PP3

REVEL = 0.798. It is above 0.75, so PP3 is met.

PM5

NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921) considered as pathogenic by these guidelines.

PM2

PopMax MAF = 0.000008790 (0.0008790%) in European (non-Finnish) (gnomAD v2.1.1). PopMax MAF < 0.02%, therefore PM2 is met.

PS3_Supporting

Functional studies (PMID: 25647241, Thormaehlen et al) using HeLa-Kyoto cells, LDLR-GFP construct, WB and CLSM assays - results - most of mutant LDLR is in ER, LDLR activity decreased compared to WT - considered as disruptive. Therefore, PS3_Supporting is met (according to FHVCEP considerations).

BA1

Since PM2 is met (PopMax MAF < 0.02%), BA1 is not met.

PS2

No de novo cases identified

PS1

No other variant with same amino acid change identified

PS4

No index cases identified.

PP1

No family members identified.

PP4

No index cases identified.

PP2

N/A according to FHVCEP guidelines

PVS1

Missense variant in LDLR exon 12.

PM3

Not identified for index cases with more than 1 variant

PM4

Missense variant in LDLR exon 12.

PM1

Variant in exon 12 of the LDLR gene (not located at exon 4)

PM6

No de novo cases identified

BS2

Not identified in normolipidemic individuals

BS4

No family members identified.

BS1

Since PM2 is met (PopMax MAF < 0.02%), BS1 is not met.

BS3

Not met, no reports

BP2

Not identified for index cases with more than 1 variant

BP3

Missense variant in LDLR exon 12.

BP4

REVEL not bellow 0.5. Therefore, BP4 is not met

BP1

N/A according to FHVCEP guidelines

BP7

Missense variant in LDLR exon 12.

BP5

N/A according to FHVCEP guidelines

Curation History

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