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_000527.4(LDLR):c.-120C>T

CA10576265

226299 (ClinVar)

Gene: N/A

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: fd6734d6-53a4-4f4f-8126-edf0993e4c4f

HGVS expressions

NM_000527.4(LDLR):c.-120C>T

NC_000019.10:g.11089429C>T

CM000681.2:g.11089429C>T

NC_000019.9:g.11200105C>T

CM000681.1:g.11200105C>T

NC_000019.8:g.11061105C>T

NG_009060.1:g.5049C>T

ENST00000558518.5:c.-120C>T

NM_000527.4:c.-120C>T

NM_001195798.1:c.-120C>T

NM_001195799.1:c.-120C>T

NM_001195800.1:c.-120C>T

NM_001195803.1:c.-120C>T

NR_163945.1:n.231G>A

Uncertain Significance

BP2 PP1 PP4 PM2 PS4_Supporting PS3_Supporting

PS2 PS1 BP3 BP4 BP1 BP5 BP7 BA1 PP3 PP2 PM3 PM1 PM4 PM5 PVS1 PM6 BS2 BS4 BS3 BS1

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 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.-120C>T variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP4, PS3_Supporting, PS4_Supporting and BP2 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: PM2 - PopMax MAF = 0.00001470 (0.001470%) in European non-Finnish (gnomAD v3.2.1). It is below 0.02%, so met. PP1 - Variant segregates with the FH phenotype in: - 2 relatives from 1 family from Francová et al. 2004 (PMID: 15303010): 2 relatives with the phenotype (LDL cholesterol concentration between 93 and 99.5 percentile for age and sex) have the variant; - 1 relative from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 1 relative without the phenotype and without the variant. 3 segregations, so PP1 is met. PS3_supporting - Level 3 FS: Francová et al. 2004 (PMID: 15303010) : Heterologous cells (HepG2), luciferase assays - results: 3% reporter gene transcription (Reported as c.-27C>T in the paper). --- it is below 50%, so PS3_Supporting is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index case with Simon Broome possible 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 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 1 index case with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia. 3 cases, so PS4_Supporting is met PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical FH criteria from different labs (please see PS4 for details), so PP4 is met. BP2 - Variant identified in 1 index case and 1 relative, both carriers of NM_000527.4(LDLR):c.2416dupG (p.Val806Glyfs*11) in trans with LDLc values of 4.3 mmol/l (16y) and 5.9 mmol/l (11y), respectively. 2nd variant is classified as Pathogenic by these guidelines and phenotype is clearly of heterozygous FH, so BP2 is met.

BP2

Variant identified in 1 index case and 1 relative, both carriers of NM_000527.4(LDLR):c.2416dupG (p.Val806Glyfs*11) in trans with LDLc values of 4.3 mmol/l (16y) and 5.9 mmol/l (11y), respectively. 2nd variant is classified as Pathogenic by these guidelines and phenotype is clearly of heterozygous FH, so BP2 is met.

PP1

Variant segregates with the FH phenotype in: - 2 relatives from 1 family from Francová et al. 2004 (PMID: 15303010): 2 relatives with the phenotype (LDL cholesterol concentration between 93 and 99.5 percentile for age and sex) have the variant; - 1 relative from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 1 relative without the phenotype and without the variant. 3 segregations, so PP1 is met

PP4

variant meets PM2 and was identified in: - 1 index case with Simon Broome possible 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 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 1 index case with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia. 3 cases, so PP4 is met

PM2

PopMax MAF = 0.00001470 (0.001470%) in European non-Finnish (gnomAD v3.2.1). It is below 0.02%, so met

PS4_Supporting

PS3_Supporting

Level 3 FS: Francová et al. 2004 (PMID: 15303010) : Heterologous cells (HepG2), luciferase assays - results: 3% reporter gene transcription (Reported as c.-27C>T in the paper). --- it is below 50%, so PS3_Supporting is met

PS2

no de novo occurrence

PS1

variant is in 5'UTR, so not applicable

BP3

not applicable

BP4

there is no in silico prediction for 5'UTR variants yet

BP1

not applicable

BP5

not applicable

BP7

variant is in 5'UTR, so not applicable

BA1

no FAF, just total MAF = 0.00001314 (0.001314%) in genomes (gnomAD v3.1.2). It is not above 0.5%, so not met

PP3

there is no in silico prediction for 5'UTR variants yet

PP2

not applicable

PM3

variant was not identified in index cases with homozygous phenotype, so not met

PM1

variant is in 5'UTR, so not applicable

PM4

variant is in 5'UTR, so not applicable

PM5

variant is in 5'UTR, so not applicable

PVS1

variant is in 5'UTR, so not applicable

PM6

no de novo occurrence

BS2

variant was not identified in 100 normolipidemic individuals from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), but was identified in 1 relative with the variant and without the phenotype (Proband published in Tichý et al. 2012, PMID: 22698793). not enough, so not met

BS4

Variant did not segregate with the FH phenotype in 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 1 relative with the variant and without the phenotype. Proband published in Tichý et al. 2012, PMID: 22698793. not enough, so not met

BS3

BS1

no FAF, just total MAF = 0.00001314 (0.001314%) in genomes (gnomAD v3.1.2). It is not above 0.2%, so not met

Approved on: 2023-04-28

Published on: 2023-05-01

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