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]

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

CA023577

161271 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

HGVS expressions

NM_000527.5:c.1775G>A

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

ENST00000558518.6:c.1775G>A

ENST00000252444.9:n.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:n.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

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

Pathogenic

PS3_Moderate PS4 PP4 PP3 PP1_Strong PM2

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

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.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).

PS3_Moderate

Level 2 assay - PMID:21865347 - study on hmz patient's lymphocytes, FACS, LDLR activity value range: 39-53%.

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).

PP4

Variant meets PM2. Variant identified in 239 index cases fulfill specific clinical criteria for FH (see PS4).

PP3

REVEL: 0,938. Score is above 0,75.

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). MAF is below 0.02%.

PVS1

Missense variant. Not applicable.

BS2

2 cases of nonsegregation - due to incomplete pentrance of 0,95. 2 nonsegregation from 49 informative meioses = 4% = OK.

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.

BS1

FAF = 0.00004735 (0.004735%) 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: 0,938. Score is not below 0,15.

BP1

Not applicable.

PS2

No de novo cases were identified.

PS1

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

BA1

FAF = 0.00004735 (0.004735%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%

PP2

Not applicable.

PM6

No de novo cases were identified.

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).

PM1

Missense at codon 592. 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 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.

Approved on: 2021-06-09

Published on: 2021-06-24

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