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.1291G>A (p.Ala431Thr)

CA023445

3695 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 77e0bdaf-bfa7-44ce-9ab5-62ba16365a7c

HGVS expressions

NM_000527.5:c.1291G>A

NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr)

NC_000019.10:g.11113382G>A

CM000681.2:g.11113382G>A

NC_000019.9:g.11224058G>A

CM000681.1:g.11224058G>A

NC_000019.8:g.11085058G>A

NG_009060.1:g.29002G>A

ENST00000558518.6:c.1291G>A

ENST00000252444.9:n.1545G>A

ENST00000455727.6:c.787G>A

ENST00000535915.5:c.1168G>A

ENST00000545707.5:c.910G>A

ENST00000557933.5:c.1291G>A

ENST00000558013.5:c.1291G>A

ENST00000558518.5:c.1291G>A

ENST00000559340.1:n.12G>A

ENST00000560173.1:n.290G>A

ENST00000560467.1:n.771G>A

NM_000527.4:c.1291G>A

NM_001195798.1:c.1291G>A

NM_001195799.1:c.1168G>A

NM_001195800.1:c.787G>A

NM_001195803.1:c.910G>A

NM_001195798.2:c.1291G>A

NM_001195799.2:c.1168G>A

NM_001195800.2:c.787G>A

NM_001195803.2:c.910G>A

Pathogenic

PS4 PS3 PP4 PP3 PM3 PM2 PP1_Strong

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

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3, 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: PS3 - Level 1 FS: Chang et al., 2003 (PMID 12837857): Heterologous cells (COS), FACS and WB assays - results: 22% LDLR expression, 20% LDL-LDLR binding and internalization, LDLR retained in endosomal/lysosomal regions. Activity is below 70% of wild-type, so PS3 is met. PS4 - variant meets PM2 and was identified in - 7 unrelated index cases (1 index case with Simon Broome possible FH and 6 index cases with DLCN >=6) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 1 index case with Simon Broome possible FH (high chol in child w/ family hx) from Ambry Genetics, USA; - 1 index case with Simon Broome possible FH (LDL-C high, family history of high cholesterol) from GeneDx Inc, USA; - 47 unrelated index cases w/ Simon Broome possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with Simon Broome possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), reported in Tichy et al. 2012 PMID: 22698793, Czech Republic; at least 57 unrelated cases, so PS4 is met. PP1_strong - variant segregates with FH phenotype in 72 informative meiosis from 28 families: - 10 informative meiosis from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): F1: 6 relatives with the variant have LDL >75th percentile, F2: 3 relatives with the variant have LDL >75th percentile, F3: 1 relative with the variant has LDL >75th percentile. - 28 informative meiosis from 14 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: in total, 21 relatives with the variant have LDL-C >75th percentile, and 7 relatives without the variant have LDL-C <50th percentile. The greatest # segregations occurring within a family is 5; - 34 informative meiosis from 11 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: in total, 20 relatives with the variant have LDL-C >75th percentile, and 14 relatives without the variant have LDL-C <50th percentile. The greatest number of segregations occurring in a family was 9 (6 relatives positive for variant w/ phenotype, and 3 relatives negative for variant w/o phenotype). --- 72 informative meiosis support co-segregation, so PP1_Strong is met PM2 - PopMax MAF = 0.00005439 (0.005%) in East Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM3 - Variant meets PM2 and was identified in - 1 index case homozygous for the variant under curation and untreated LDL = 512mg/dL from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. ----- it is an homozygous patient with an homozygous phenotype, so PM3 is met. PP3 - REVEL = 0.914. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in at least 57 unrelated cases (see PS4 for details), so PP4 is met.

PS4

variant meets PM2 and was identified in - 7 unrelated index cases (1 index case with Simon Broome possible FH and 6 index cases with DLCN >=6) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 1 index case with Simon Broome possible FH (PT4: high chol in child w/ family hx) from Ambry Genetics, USA; - 1 index case with Simon Broome possible FH (LDL-C 242, family history of high cholesterol) from GeneDx Inc, USA; - 47 unrelated index cases w/ Simon Broome possible FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal; - 1 index case with Simon Broome possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), reported in Tichy et al. 2012 PMID: 22698793, Czech Republic; at least 57 unrelated cases (no additional bibliographic search was done because number of cases is already over 10), so PS4 is met.

PS3

Level 1 FS: Chang et al., 2003 (PMID 12837857): Heterologous cells (COS), FACS and WB assays - results: 22% LDLR expression, 20% LDL-LDLR binding and internalization, LDLR retained in endosomal/lysosomal regions. Activity is below 70% of wild-type, so PS3 is met. Level 2(Pathogenic) FS: Hobbs et al., 1990 (PMID 2088165): Hmz patient fibroblast, 125I-LDL assays - results: 5-15% LDLR activity. Activity is below 70%, so PS3_Moderate would be met, but PS3 is already met.

PP4

PP3

REVEL = 0.914. It is above 0.75, so PP3 is met

PM3

Variant meets PM2 and was identified in - 1 index case with also NM_000527.5(LDLR):c.313+6T>C, confirmed to be in trans and LDL = 435mg/dL (unknown if on medications) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. --- 2nd variant is classified as VUS by these guidelines. But phenotype is not clearly heterozygous nor homozygous, so do not consider for PM3. - 1 index case homozygous for the variant under curation and untreated LDL = 512mg/dL from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. ----- it is an homozygous patient with an homozygous phenotype, so PM3 is met

PM2

PopMax MAF = 0.00005439 (0.005%) in East Asian exomes (gnomAD v2.1.1).. It is below 0.02%, so PM2 is met

PP1_Strong

variant segregates with FH phenotype in 72 informative meiosis from 28 families: - 10 informative meiosis from 3 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): F1: 6 relatives with the variant have LDL >75th percentile, F2: 3 relatives with the variant have LDL >75th percentile, F3: 1 relative with the variant has LDL >75th percentile. - 28 informative meiosis from 14 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: in total, 21 relatives with the variant have LDL-C >75th percentile, and 7 relatives without the variant have LDL-C <50th percentile. The greatest # segregations occurring within a family is 5; - 34 informative meiosis from 11 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo: in total, 20 relatives with the variant have LDL-C >75th percentile, and 14 relatives without the variant have LDL-C <50th percentile. The greatest number of segregations occurring in a family was 9 (6 relatives positive for variant w/ phenotype, and 3 relatives negative for variant w/o phenotype). 72 informative meiosis support co-segregation, so PP1_Strong is met

PS2

no de novo occurrence

PS1

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

BA1

no FAF, just total MAF = 0.000003980 (0.0004%) in East Asian exomes (gnomAD v2.1.1). It is not above 0.5%, so BA1 is not met

PVS1

variant is missense and not on inititation codon, so PVS1 is not met

PP2

not applicable

PM1

variant is not on exon 4 and does not alter Cys, so PM1 is not met

PM4

variant is missense, not applicable

PM5

1 more missense variant in the same codon: - NM_000527.4(LDLR):c.1291G>C (p.Ala431Pro) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(1);Uncertain significance(1) in ClinVar - Likely pathogenic by these guidelines so PM5 is not met

PM6

no de novo occurrence

BS2

variant was - not identified in 0/190 non-FH alleles from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; - not identified in 0/100 normolipidemic individuals from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); - identified in 2 relatives, 1 from each family, with <50th percentile LDL from Laboratory of Genetics and Molecular Cardiology, University of São Paulo, Brazil, not enough, so not met.

BS4

variant does not segregate with FH phenotype in 4 informative meiosis from 3 families: - 4 non-segregations from 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge - 4 relatives (2+1+1) with the phenotype do not have the variant. - 4 non-segregations from 4 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo - each family with 1 non-segregation: 2 relatives with variant and <50th percentile LDL and 2 relatives without the variant and >75th percentile LDL not one family with 2 non-segregations, so BS4 is not met

BS3

Level 1 FS: Chang et al., 2003 (PMID 12837857): Heterologous cells (COS), FACS and WB assays - results: 22% LDLR expression, 20% LDL-LDLR binding and internalization, LDLR retained in endosomal/lysosomal regions. Activity is not above 90% of wild-type, so BS3 is not met. Level 3(Benign) FS: Hobbs et al., 1990 (PMID 2088165): Hmz patient fibroblast, 125I-LDL assays - results: 5-15% LDLR activity. Activity is not above 90%, so BS3_Supporting is not met.

BS1

no FAF, just total MAF = 0.000003980 (0.0004%) in East Asian exomes (gnomAD v2.1.1). It is not above 0.2%, so BS1 is not met

BP2

Variant was identified in - 1 index case with also NM_000527.5(LDLR):c.313+6T>C, confirmed to be in trans and LDL = 435mg/dL (unknown if on medications) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. --- 2nd variant is classified as VUS by these guidelines. But phenotype is not clearly heterozygous nor homozygous, so do not consider for BP2.

BP3

not applicable

BP4

REVEL = 0.914. It is not below 0.50, so BP4 is not met

BP1

not applicable

BP5

not applicable

BP7

variant is missense, not applicable

Approved on: 2022-08-28

Published on: 2022-08-28

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