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.1640T>C (p.Leu547Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585539

251949 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7e5fa005-861b-4c10-be16-030c1864ee4c

Approved on: 2024-08-30

Published on: 2024-10-09

HGVS expressions

NM_000527.5:c.1640T>C

NM_000527.5(LDLR):c.1640T>C (p.Leu547Pro)

NC_000019.10:g.11116147T>C

CM000681.2:g.11116147T>C

NC_000019.9:g.11226823T>C

CM000681.1:g.11226823T>C

NC_000019.8:g.11087823T>C

NG_009060.1:g.31767T>C

ENST00000252444.10:c.1898T>C

ENST00000559340.2:c.1640T>C

ENST00000560467.2:c.1520T>C

ENST00000558518.6:c.1640T>C

ENST00000252444.9:c.1894T>C

ENST00000455727.6:c.1136T>C

ENST00000535915.5:c.1517T>C

ENST00000545707.5:c.1259T>C

ENST00000557933.5:c.1640T>C

ENST00000558013.5:c.1640T>C

ENST00000558518.5:c.1640T>C

ENST00000559340.1:c.361T>C

NM_000527.4:c.1640T>C

NM_001195798.1:c.1640T>C

NM_001195799.1:c.1517T>C

NM_001195800.1:c.1136T>C

NM_001195803.1:c.1259T>C

NM_001195798.2:c.1640T>C

NM_001195799.2:c.1517T>C

NM_001195800.2:c.1136T>C

NM_001195803.2:c.1259T>C

Uncertain Significance

PS4_Supporting PP3 PP4 PM2

PS2 PS3 PS1 BP5 BP7 BP2 BP3 BP4 BP1 PP1 PP2 PVS1 PM1 PM3 PM4 PM5 PM6 BA1 BS4 BS3 BS1 BS2

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.1640T>C (p.Leu547Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: MAF=8.477e-7 (0.000085%) in European (non-Finnish) exomes (gnomAD v4.1.0). PP3: REVEL=0.883. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH (1 case with DLCN score >=6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, USA; 2 cases with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism, Italy).

PS4_Supporting

Variant meets PM2 and is identified in 3 unrelated index cases (1 case with DLCN>=6 criteria for FH from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, USA; 2 cases with DLCN>=6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism, Italy), so PS4_Supporting is met

PP3

REVEL = 0.883.

PP4

PM2

PopMax MAF = 8.477e-7 (0.000085%) in European (non-Finnish) exomes (gnomAD V4.1.0). It is below 0.02%, so met

PS2

no de novo occurrence

PS3

no published functional studies

PS1

No other variant in the same codon, so not met

BP5

not applicable

BP7

missense, so not applicable

BP2

not identified in index cases with more than 1 variant

BP3

not applicable

BP4

REVEL = 0.883.

BP1

Not applicable

PP1

Variant segregates with FH phenotype in 1 informative meiosis in 1 family (PMID: 28161202) - for PP1, the minimum of 2 meiosis is necessary

PP2

Not applicable

PVS1

missense and not in initiation codon, so not applicable

PM1

Variant meets PM2 but it is not located in exon 4, and it is not one of 60 highly conserved cysteine residues.

PM3

not identified in index cases with more than 1 variant

PM4

missense, so not applicable

PM5

No other variant in the same codon, so not met

PM6

no de novo occurrence

BA1

no FAF, just total MAF = 6.197e-7 (0.00006197%) in exomes (gnomAD v4.1.0). It is not above 0.5%, so not met

BS4

no lack of segregation identified

BS3

no published functional studies

BS1

no FAF, just total MAF = 6.197e-7 (0.00006197%) in exomes (gnomAD v4.1.0). It is not above 0.2%, so not met

BS2

not identified in normolipidemic individuals

Curation History

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