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.1222G>A (p.Glu408Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023437

36453 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e08d34fe-2556-4636-864a-0cc996c545c4

Approved on: 2021-06-09

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1222G>A

NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)

NC_000019.10:g.11113313G>A

CM000681.2:g.11113313G>A

NC_000019.9:g.11223989G>A

CM000681.1:g.11223989G>A

NC_000019.8:g.11084989G>A

NG_009060.1:g.28933G>A

ENST00000558518.6:c.1222G>A

ENST00000252444.9:n.1476G>A

ENST00000455727.6:c.718G>A

ENST00000535915.5:c.1099G>A

ENST00000545707.5:c.841G>A

ENST00000557933.5:c.1222G>A

ENST00000558013.5:c.1222G>A

ENST00000558518.5:c.1222G>A

ENST00000560173.1:n.221G>A

ENST00000560467.1:n.702G>A

NM_000527.4:c.1222G>A

NM_001195798.1:c.1222G>A

NM_001195799.1:c.1099G>A

NM_001195800.1:c.718G>A

NM_001195803.1:c.841G>A

NM_001195798.2:c.1222G>A

NM_001195799.2:c.1099G>A

NM_001195800.2:c.718G>A

NM_001195803.2:c.841G>A

Likely Pathogenic

PS3_Moderate PM2 PS4_Moderate PP4 PP1 PP3

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

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate, PP1, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity. PS4_moderate - Variant meets PM2. Variant identified in 8 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria). PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL: 0,879. Score is above 0,75. PP4 - Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate).

PS3_Moderate

Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity.

PM2

PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.

PS4_Moderate

Variant meets PM2. Variant identified in 8 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria).

PP4

Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate).

PP1

Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.

PP3

REVEL: 0,879. Score is above 0,75.

PM3

Not identified in individuals with other variants.

PM1

Missense at codon 408. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.

PM4

Missense variant. Not applicable.

PM5

No other missense variants in the same codon classified as Pathogenic by these guidelines. Four missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.4(LDLR):c.1222G>C (p.Glu408Gln) (ClinVar ID 373430) - classified as VUS by these guidelines; (2)NM_000527.5(LDLR):c.1223A>T (p.Glu408Val) (ClinVar ID 251740) - classified as Likely pathogenic by these guidelines; (3)NM_000527.5(LDLR):c.1223A>C (p.Glu408Ala) (ClinVar ID 251739) - classified as Likely pathogenic by these guidelines; (4)NM_000527.4(LDLR):c.1224G>C (p.Glu408Asp) (ClinVar ID 431524) - classified as VUS by these guidelines.

PM6

No de novo cases were identified.

BA1

FAF = 0.000002930 (0.0002930%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%.

BS2

No unaffected individuals identified with the variant.

PVS1

Missense variant. Not applicable.

BS4

1 case of non-segregation was identified. At least 2 cases in at least 2 families are needed.

BS3

Level 3 FS: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 3 FS: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity.

BS1

FAF = 0.000002930 (0.0002930%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%.

BP2

Not identified in individuals with other variants.

BP3

Not applicable.

BP4

REVEL: 0,879. Score is not below 0,15.

BP1

Not applicable.

BP5

Not applicable.

BP7

Missense variant. Not applicable.

PS2

No de novo cases were identified.

PS1

No variant described that leads to the same amino acid change.

PP2

Not applicable.

Curation History

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