Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)

CA023437

36453 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: e08d34fe-2556-4636-864a-0cc996c545c4

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 6
PS4_Moderate PS3_Moderate PP4 PP1 PP3 PM2
Not Met criteria codes 20
PS2 PS1 PP2 PM6 PM3 PM1 PM4 PM5 BA1 BS2 PVS1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 0

Expert Panel

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).
Met criteria codes
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).
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.
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.
PM2
PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.
Not Met criteria codes
PS2
No de novo cases were identified.
PS1
No variant described that leads to the same amino acid change.
PP2
Not applicable.
PM6
No de novo cases were identified.
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.
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%.
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
REVEL: 0,879. Score is not below 0,15.
BP1
Not applicable.
Approved on: 2021-06-09
Published on: 2021-06-24
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