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]
  • See Evidence submitted by expert panel for details.

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
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
ENST00000252444.10:c.1480G>A
ENST00000559340.2:c.1222G>A
ENST00000560467.2:c.1102G>A
ENST00000558518.6:c.1222G>A
ENST00000252444.9:c.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:c.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
More

Likely Pathogenic

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

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
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).
PM2
PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.
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).
Not Met criteria codes
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BP4
REVEL: 0,879. Score is not below 0,15.
BP3
Not applicable.
BP1
Not applicable.
BP2
Not identified in individuals with other variants.
PS1
No variant described that leads to the same amino acid change.
PS2
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.
PM1
Missense at codon 408. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
PM3
Not identified in individuals with other variants.
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.
PM4
Missense variant. Not applicable.
PM6
No de novo cases were identified.
BS1
FAF = 0.000002930 (0.0002930%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%.
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.
BS2
No unaffected individuals identified with the variant.
PVS1
Missense variant. Not applicable.
Curation History
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