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.1748A>G (p.His583Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585595

252012 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e544d995-1e9d-46dd-ab67-e144025f2189

Approved on: 2023-11-07

Published on: 2024-12-24

HGVS expressions

NM_000527.5:c.1748A>G

NM_000527.5(LDLR):c.1748A>G (p.His583Arg)

NC_000019.10:g.11116901A>G

CM000681.2:g.11116901A>G

NC_000019.9:g.11227577A>G

CM000681.1:g.11227577A>G

NC_000019.8:g.11088577A>G

NG_009060.1:g.32521A>G

ENST00000252444.10:c.2006A>G

ENST00000559340.2:c.1705+689A>G

ENST00000560467.2:c.1628A>G

ENST00000558518.6:c.1748A>G

ENST00000252444.9:c.2002A>G

ENST00000455727.6:c.1244A>G

ENST00000535915.5:c.1625A>G

ENST00000545707.5:c.1367A>G

ENST00000557933.5:c.1748A>G

ENST00000558013.5:c.1748A>G

ENST00000558518.5:c.1748A>G

ENST00000559340.1:c.426+689A>G

NM_000527.4:c.1748A>G

NM_001195798.1:c.1748A>G

NM_001195799.1:c.1625A>G

NM_001195800.1:c.1244A>G

NM_001195803.1:c.1367A>G

NM_001195798.2:c.1748A>G

NM_001195799.2:c.1625A>G

NM_001195800.2:c.1244A>G

NM_001195803.2:c.1367A>G

Likely Pathogenic

PP4 PP3 PM5 PM2

PS2 PS4 PS1 PS3 PP1 PP2 PM3 PM4 PM1 PM6 BA1 PVS1 BS1 BS3 BP7 BP5 BP2 BP3 BP4 BP1

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.1748A>G (p.His583Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.819. 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). PP4: Variant meets PM2 and is identified in at least 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic (PMID 22698793, Tichý et al., 2012).

PP4

Variant meets PM2 and is identified in at least 1 index case fulfilling SB criteria for possible FH, after alternative causes of high cholesterol are excluded from the Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), This index case is published in PMID: 22698793

PP3

REVEL = 0.819. 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

This variant is absent from gnomAD (gnomAD v2.1.1).

PS2

No de novo occurrence

PS4

PS4_Supporting: 1 index case (PMID:2698793) fulfilling SB criteria or untreated total and/or LDL levels above P95th of age/sex/population not considered to avoid double-counting.

PS1

No other variant with same amino acid change identified

PS3

Functional studies (PMID: 32695144) performed using Heterologous cells (CHO), WB and FACS - results - 77% expression and 80% internalisation. ----- Overall, the results are not below 70%, so PS3 is not met.

PP1

Variant segregates with FH phenotype in 1 informative meiose (only 1 family) from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) - 1 relative does not have the variant and has LDL<50th percentile.

PP2

N/A according to FHVCEP guidelines

PM3

Not identified in index cases with more than one variant

PM4

Missense variant - LDLR exon 12

PM1

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

PM6

No de novo occurrence

BA1

This variant is absent from gnomAD (gnomAD v2.1.1).

PVS1

Missense variant - LDLR exon 12

BS1

This variant is absent from gnomAD (gnomAD v2.1.1).

BS3

Functional studies (PMID: 32695144) performed using Heterologous cells (CHO), WB and FACS - results - 77% expression and 80% internalisation. ----- Overall, results are not above 90/95%, so BS3 is not met either.

BP7

Missense variant - LDLR exon 12

BP5

N/A according to FHVCEP guidelines

BP2

Not identified in index cases with more than one variant

BP3

Missense variant - LDLR exon 12

BP4

REVEL = 0.819. It is not bellow 0.5, so BP4 is not met.

BP1

N/A according to FHVCEP guidelines

Curation History

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