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.1048C>T (p.Arg350Ter)

CA031387

226342 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: bf884b04-1e33-40c4-997c-e13fd8755871

HGVS expressions

NM_000527.5:c.1048C>T

NM_000527.5(LDLR):c.1048C>T (p.Arg350Ter)

NC_000019.10:g.11110759C>T

CM000681.2:g.11110759C>T

NC_000019.9:g.11221435C>T

CM000681.1:g.11221435C>T

NC_000019.8:g.11082435C>T

NG_009060.1:g.26379C>T

ENST00000558518.6:c.1048C>T

ENST00000252444.9:n.1302C>T

ENST00000455727.6:c.544C>T

ENST00000535915.5:c.925C>T

ENST00000545707.5:c.667C>T

ENST00000557933.5:c.1048C>T

ENST00000558013.5:c.1048C>T

ENST00000558518.5:c.1048C>T

ENST00000560173.1:n.47C>T

ENST00000560467.1:n.541-755C>T

NM_000527.4:c.1048C>T

NM_001195798.1:c.1048C>T

NM_001195799.1:c.925C>T

NM_001195800.1:c.544C>T

NM_001195803.1:c.667C>T

NM_001195798.2:c.1048C>T

NM_001195799.2:c.925C>T

NM_001195800.2:c.544C>T

NM_001195803.2:c.667C>T

Pathogenic

PS4 PM2 PP1_Strong PVS1 PP4

PS3 BS4

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.1048C>T(p.Arg350Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1, PP4, PS4, PP1_Strong) 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 = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1). PVS1: The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830). PP4: This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4: Variant meets PM2 and is identified in 23 unrelated index cases fulfil clinical criteria for FH. Ten cases fulfil Simon Broome FH criteria (5 cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; 3 cases from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, PMID 22698793; 1 case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 1 case from Division of Cardiology, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (PMID 20538126)). Thirteen cases fulfil DLCN criteria (10 cases from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; 1 case each from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain (PMID 19318025); Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland (PMID 9654205); GeneDx). PP1_Strong: Variant segregates with FH phenotype in 20 informative meiosis from at least 11 families. Fifteen affected relatives tested positive for the variant from at least 6 families from 4 different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation; GeneDx; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Five unaffected relatives tested negative for the variant from 5 families (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA).

PS4

Variant meets PM2 and is identified in 23 unrelated index cases fulfil clinical criteria for FH. Ten cases fulfil Simon Broome FH criteria (5 cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; 3 cases from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, PMID 22698793; 1 case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 1 case from Division of Cardiology, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (PMID 20538126)). Thirteen cases fulfil DLCN criteria (10 cases from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; 1 case each from Lipid Clinic, Fundación Jiménez Díaz, Madrid, Spain (PMID 19318025); Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland (PMID 9654205); GeneDx).

PM2

PopMax MAF = 0.00005 in East Asian population in gnomAD (gnomAD v2.1.1).

PP1_Strong

Variant segregates with FH phenotype in 20 informative meiosis from at least 11 families. Fifteen affected relatives tested positive for the variant from at least 6 families from 4 different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation; GeneDx; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). Five unaffected relatives tested negative for the variant from 5 families (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA).

PVS1

The variant causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830).

PP4

This variant meets PM2 and is identified in >1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.

PS3

Functional data is not available.

BS4

Variant does not segregate with FH phenotype in 3 relatives in 3 families from 3 different labs. Three affected relatives tested negative for the variant, 1 case each from: Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA; Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. However, there is no instance where unaffected family member carry the variant. Therefore BS4 is not met.

Approved on: 2022-03-25

Published on: 2022-04-25

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