Variant: NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)

CA023577

161271 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: cd0c4aea-7158-4181-83f0-1c4cce449e45

Approved on: 2021-06-09

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1775G>A
NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu)
NC_000019.10:g.11116928G>A
CM000681.2:g.11116928G>A
NC_000019.9:g.11227604G>A
CM000681.1:g.11227604G>A
NC_000019.8:g.11088604G>A
NG_009060.1:g.32548G>A
ENST00000252444.10:c.2033G>A
ENST00000559340.2:c.1705+716G>A
ENST00000560467.2:c.1655G>A
ENST00000558518.6:c.1775G>A
ENST00000252444.9:c.2029G>A
ENST00000455727.6:c.1271G>A
ENST00000535915.5:c.1652G>A
ENST00000545707.5:c.1394G>A
ENST00000557933.5:c.1775G>A
ENST00000558013.5:c.1775G>A
ENST00000558518.5:c.1775G>A
ENST00000559340.1:c.426+716G>A
NM_000527.4:c.1775G>A
NM_001195798.1:c.1775G>A
NM_001195799.1:c.1652G>A
NM_001195800.1:c.1271G>A
NM_001195803.1:c.1394G>A
NM_001195798.2:c.1775G>A
NM_001195799.2:c.1652G>A
NM_001195800.2:c.1271G>A
NM_001195803.2:c.1394G>A

Pathogenic

• Met criteria codes: PS4 PP3 PP4 PM2 PP1_Strong PS3_Moderate

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

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM2, PS3_Moderate, 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: PS4 - Variant meets PM2. Variant identified in 239 index cases. PP1_strong - 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PM2 - PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%. PP3 - REVEL: 0,938. PP4 - Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).

Met criteria codes

• PS4: Variant meets PM2. Variant identified in 239 index cases (3 cases with Simon-Broome from Color laboratory; 189 cases with MedPed criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 5 cases with Simon-Broome criteria from GeneDx; 15 cases with Siom-Broome criteria from Laboratory of Genetics and Molecular Cardiology; 2 cases with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 6 cases with DLCN criteria from University of British Columbia; 19 cases with Simon-Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
• PP3: REVEL: 0,938. Score is above 0,75.
• PP4: Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (see PS4).
• PM2: PopMax MAF = 0.0001161 (0.012%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.
• PP1_Strong: 130 informative meioses (1 from Robarts Research Institute; 83 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 19 from Laboratory of Genetics and Molecular Cardiology; 2 from University of British Columbia; 25 from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
• PS3_Moderate: Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%.

Not Met criteria codes

• PS1: No variant described that leads to the same amino acid change.
• PS2: No de novo cases were identified.
• PP2: Not applicable.
• PM6: No de novo cases were identified.
• PVS1: Missense variant. Not applicable.
• PM1: Missense at codon 592. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.
• PM3: 2 cases of homozygozity (LDLc: 9.95 mmol/l and 9.99 mmol/l respectively - not fulfill the levels for HoFH defined as LDL above 500mg/dl. untreated values of index case 19 are TC of 600mg/dl); 5 cases of compound heterozygozity (no proven pathogenic variants in double).
• PM5: No other missense variants classified as Pathogenic in the same codon. One other missense variant described in the same codon (accessed 19 August 2020): (1)NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) (ClinVar ID 373769) - classified as VUS by these guidelines.
• PM4: Missense variant. Not applicable.
• BA1: FAF = 0.00004735 (0.004735%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%
• BS2: 2 cases of nonsegregation - due to incomplete pentrance of 0,95. 2 nonsegregation from 49 informative meioses = 4% = OK.
• BS1: FAF = 0.00004735 (0.004735%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%
• BS4: Total 7 nonsegregations - VCEP LDLR guidelines needs at least 2 cases in at least 2 families. All reported non-segregation arised from isolated cases in separated families.
• BS3: No functional study showing non-damaging effect on protein function or splicing.
• BP5: Not applicable.
• BP7: Missense variant. Not applicable.
• BP4: REVEL: 0,938. Score is not below 0,15.
• BP3: Not applicable.
• BP1: Not applicable.
• BP2: Not identified in individuals with other variants.