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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.418G>A (p.Glu140Lys)

CA10584911

251213 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: d63fb472-1e90-49ec-afe1-e4d3de7005aa

HGVS expressions

NM_000527.5:c.418G>A

NM_000527.5(LDLR):c.418G>A (p.Glu140Lys)

NC_000019.10:g.11105324G>A

CM000681.2:g.11105324G>A

NC_000019.9:g.11216000G>A

CM000681.1:g.11216000G>A

NC_000019.8:g.11077000G>A

NG_009060.1:g.20944G>A

ENST00000558518.6:c.418G>A

ENST00000252444.9:n.672G>A

ENST00000455727.6:c.314-2068G>A

ENST00000535915.5:c.295G>A

ENST00000545707.5:c.314-1241G>A

ENST00000557933.5:c.418G>A

ENST00000558013.5:c.418G>A

ENST00000558518.5:c.418G>A

ENST00000560467.1:n.18G>A

NM_000527.4:c.418G>A

NM_001195798.1:c.418G>A

NM_001195799.1:c.295G>A

NM_001195800.1:c.314-2068G>A

NM_001195803.1:c.314-1241G>A

NM_001195798.2:c.418G>A

NM_001195799.2:c.295G>A

NM_001195800.2:c.314-2068G>A

NM_001195803.2:c.314-1241G>A

Pathogenic

PS4_Supporting PP4 PP3 PM2 PM1 PP1_Strong

PS2 PS3 PS1 PP2 PM6 PM3 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.418G>A (p.Glu140Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 8 informative meioses from 4 families from Instituto Nacional de Saude Doutor Ricardo Jorge and Laboratory of Genetics and Molecular Cardiology, so PP1_Strong is met. PM1 - variant is missense in exon 4 and meets PM2 criteria, so PM1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.965, it is above 0.75, so PP3 is met. PP4 - Variant meets PM2 and was identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met. PS4_supporting - variant meets PM2. Identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, PS4_supporting is met.

PS4_Supporting

variant meets PM2. Identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, PS4_supporting is met

PP4

Variant meets PM2 and was identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met

PP3

REVEL = 0.965, it is above 0.75, so PP3 is met

PM2

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

PM1

variant is missense in exon 4 and meets PM2 criteria, so PM1 is met

PP1_Strong

variant segregates with FH phenotype in 8 informative meioses from 4 families: - 2 families, each with 1 affected relative (LDLC>75th) with variant from Instituto Nacional de Saude Doutor Ricardo Jorge - 2 families: Family 1: 3 affected relatives (LDLC>75th) with the variant, Family 2: 2 affected relatives (LDLC>75th) with the variant plus 1 unaffected relative (LDLC<50th) without the variant, from Laboratory of Genetics and Molecular Cardiology ---- so PP1_Strong is met

PS2

no de novo occurence identified

PS3

variant was not studied in functional studies yet

PS1

PM1 is met, so PS1 cannot be met.

PP2

not applicable

PM6

no de novo occurence identified

PM3

no index case with homozygous phenotype

PM4

variant is missense, so not applicable

PM5

PM1 is met, so PM5 cannot be met.

PVS1

variant is missense and not on initiation codon, so not applicable

BA1

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

BS2

variant is not identified in normolipidemic individuals: 0/190 non-FH alleles from Instituto Nacional de Saude Doutor Ricardo Jorge, not met

BS4

no lack of segregation was identified, so not met

BS3

variant was not studied in functional studies yet

BS1

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

BP5

not applicable

BP7

variant is not synonymous, not applicable

BP2

variant identified in 1 index case from Instituto Nacional de Saude Doutor Ricardo Jorge with LDL = 229mg/dl and also LDLR NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr) - 2 stars, Benign/Likely benign - Benign by these guidelines BP2 is not met

BP3

not applicable

BP4

REVEL = 0.965, it is not below 0.50, so BP4 is not met

BP1

not applicable

Approved on: 2021-12-13

Published on: 2022-07-11

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