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

CA023437

36453 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

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

• Met criteria codes: PS3_Moderate PS4_Moderate PM2 PP4 PP1 PP3

• Not Met criteria codes: BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS1 PM3 PM1 PM4 PM5 PM6 BA1 PP2 PVS1 BS2 BS4 BS3 BS1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

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).

Met criteria codes

• 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).
• PM2: PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.
• 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.

Not Met criteria codes

• 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.
• 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%.
• PP2: Not applicable.
• PVS1: Missense variant. Not applicable.
• BS2: No unaffected individuals identified with the variant.
• 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%.