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Variant: NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg)

CA023495

161277 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: d3424058-b37e-4bce-b932-0695abc3af1d

Approved on: 2021-12-14

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.1432G>A

NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg)

NC_000019.10:g.11113608G>A

CM000681.2:g.11113608G>A

NC_000019.9:g.11224284G>A

CM000681.1:g.11224284G>A

NC_000019.8:g.11085284G>A

NG_009060.1:g.29228G>A

ENST00000558518.6:c.1432G>A

ENST00000252444.9:n.1686G>A

ENST00000455727.6:c.928G>A

ENST00000535915.5:c.1309G>A

ENST00000545707.5:c.1051G>A

ENST00000557933.5:c.1432G>A

ENST00000558013.5:c.1432G>A

ENST00000558518.5:c.1432G>A

ENST00000559340.1:n.153G>A

ENST00000560467.1:n.912G>A

NM_000527.4:c.1432G>A

NM_001195798.1:c.1432G>A

NM_001195799.1:c.1309G>A

NM_001195800.1:c.928G>A

NM_001195803.1:c.1051G>A

NM_001195798.2:c.1432G>A

NM_001195799.2:c.1309G>A

NM_001195800.2:c.928G>A

NM_001195803.2:c.1051G>A

Pathogenic

PS4 PP4 PP3 PM2 PP1_Strong

BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 BA1 PP2 PM6 PM3 PM1 PM4 PM5 PVS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS4, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs: - Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile; - Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant. so PP1_Strong is met PS4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs: - 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory), so PS4 is met PM2 - PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4), so PP4 is met.

PS4

variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs: - 1 case with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - 1 case with DLCN score >= 6 from Color Health, Inc; - 4 unrelated cases with DLCN score >= 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 4 unrelated cases with Simon-Broome criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; - 1 case with DLCN score >= 6 from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory). so PS4 is met

PP4

variant meets PM2 and was identified in at least 11 unrelated index cases who fulfill clinical FH criteria from different labs (see details in PS4) so PP4 is met

PP3

REVEL = 0.985. It is above 0.75, so PP3 is met

PM2

PopMax MAF = 0.0001234 (0.01234%) in African/African-American exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

PP1_Strong

variant segregates with FH phenotype in 10 informative meiosis from 4 families from 2 labs: - Laboratory of Genetics and Molecular Cardiology - Data from 1 family: 2 relatives positive for variant with LDL-C >75th percentile, 1 relative negative for variant with LDL-C <50th percentile; - Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge - Data from 3 families. F1: 3 relatives with the phenotype are positive for the variant plus 1 relative without the phenotype is negative for the variant. F2: 1 relative with the phenotype and positive for the variant plus 1 relative without the phenotype is negative for the variant. F3: 1 relative with the phenotype is positive for the variant. so PP1_Strong is met

BS4

only 1 non-segregation was identified: 1 relative negative for variant with LDL-C >75th percentile from Laboratory of Genetics and Molecular Cardiology , not enough, so BS4 is not met

BS3

this variant was not studied in published functional studies yet

BS1

FAF = 0.00002138 (0.002%) in African/African-American exomes (gnomAD v2.1.1). It is not above 0.2%, so BS1 is not met

BS2

not identified in normolipidemic individuals: 0/104 non-FH individuals from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge and 0/100 normolipidemic individuals from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so BS2 is not met

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

1 index case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) (with DLCS >=6) is also heterozygous for NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) and has a phenotype of HeFH. - 2 stars, Uncertain significance - VUS by these guidelines 1 index case from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies also have LDLR, c.-168-100G>T, p.?, - but no phenotype, so not applicable; 1 index case from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies also have LDLR, c.1135T>C, p.Cys379Arg, - but no phenotype, so not applicable; 1 index case from Ambry with LDL pretreatment >400 is also het for LDLR p.V429M variant (phase unknown) - phenotype is not below 350mg/dl, so not applicable 1 index case from Ambry with LDL 268mg/dl is also het for APOB p.Y1247C - VUS, which is leaning VLB per lab no index case with heterozygous phenotype was identified with another pathogenic variant, so not met

BP3

not applicable

BP4

REVEL = 0.985. It is not below 0.50, so BP4 is not met

BP1

not applicable

PS2

no de novo occurrence identified

PS3

this variant was not studied in published functional studies yet

PS1

no other variant leads to the same amino acid change, so PS1 is not met

BA1

FAF = 0.00002138 (0.002%) in African/African-American exomes (gnomAD v2.1.1). It is not above 0.5%, so BA1 is not met

PP2

not applicable

PM6

no de novo occurrence identified

PM3

1 index case from Ambry with LDL pretreatment >400 is also het for LDLR p.V429M variant (phase unknown) - phenotype is not above 500mg/dl, so not applicable so not met

PM1

variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so PM1 is not met

PM4

variant is missense, so not applicable

PM5

2 other missense variants in the same codon: - NM_000527.4(LDLR):c.1432G>T (p.Gly478Trp) - 1 star, Uncertain significance - VUS by these guidelines - NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) - 0 stars, Pathogenic - VUS by these guidelines no Pathogenic with these guidelines, so PM5 is not met

PVS1

variant is missense and not in initiation codon, so PVS1 is not met

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