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Variant: NM_000527.5(LDLR):c.1916T>A (p.Val639Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023607

200922 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 76d64ef3-260a-4724-8567-92a57e6c92d3

Approved on: 2025-01-31

Published on: 2025-03-09

HGVS expressions

NM_000527.5:c.1916T>A

NM_000527.5(LDLR):c.1916T>A (p.Val639Asp)

NC_000019.10:g.11120162T>A

CM000681.2:g.11120162T>A

NC_000019.9:g.11230838T>A

CM000681.1:g.11230838T>A

NC_000019.8:g.11091838T>A

NG_009060.1:g.35782T>A

ENST00000252444.10:c.2174T>A

ENST00000559340.2:c.1776T>A

ENST00000560467.2:c.1796T>A

ENST00000558518.6:c.1916T>A

ENST00000252444.9:c.2170T>A

ENST00000455727.6:c.1412T>A

ENST00000535915.5:c.1793T>A

ENST00000545707.5:c.1535T>A

ENST00000557933.5:c.1916T>A

ENST00000558013.5:c.1916T>A

ENST00000558518.5:c.1916T>A

ENST00000559340.1:c.497T>A

NM_000527.4:c.1916T>A

NM_001195798.1:c.1916T>A

NM_001195799.1:c.1793T>A

NM_001195800.1:c.1412T>A

NM_001195803.1:c.1535T>A

NM_001195798.2:c.1916T>A

NM_001195799.2:c.1793T>A

NM_001195800.2:c.1412T>A

NM_001195803.2:c.1535T>A

Pathogenic

PS4 PP4 PP1 PM3 PM2

BP2 BP4 BP7 PS1 PS2 PS3 PVS1 PP3 PM5 PM4 PM1 PM6 BA1 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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PM3, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PS4, PP4: Variant meets PM2 and is identified in 10 unrelated index cases from different labs (2 cases with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 1 case with DLCN>=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with DLCN>=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with DLCN=9 from Germany (PMID 11462246 – Nauck et al., 2001); at least 1 case with definite FH from The Netherlands (PMID 16250003 – Fouchier et al., 2005); 1 case with DLCN>=6 from Argentina (PMID 28502510 – Bañares et al., 2017); 1 case with Simon Broome criteria for FH from Poland (PMID 35741760 – Rutkowska et al. 2022); 1 true homozygous case with clinical diagnosis of HoFH from Spain (PMID 27784735); 1 case with homozygous FH phenotype (LDL-C= 13.52 mmol/L) from Germany (PMID 29502162). PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic: 2 affected family members have the variant. PM3: Variant meets PM2 and is identified in 1 index case with homozygous FH phenotype (LDL-C=11.7 mmol/L) and LDLR c. 2043C>T/p.(Cys681*), classified as Pathogenic by these guidelines, in trans, from Germany (PMID 29502162 – Klaus et al., 2018).

PS4

Variant meets PM2 and is identified in 10 unrelated index cases from different labs (2 cases with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies; 1 case with DLCN>=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with DLCN>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN=9 from Germany (PMID: 11462246); at least 1 case with definite heterozygous hypercholesterolemia from The Netherlands (PMID: 16250003); 1 case with DLCN>=6 from Argentina (PMID: 28502510); 1 case with Simon Broome criteria for FH from Poland (PMID: 35741760); 1 true homozygous with clinical diagnosis of HoFH from Spain (PMID: 27784735); 1 index case with homozygous FH phenotype (LDL-C= 13.52 mmol/L) from Germany, so PS4 is met.

PP4

PP1

Variant segregates with FH phenotype in 3 informative meiosis from 2 families from different labs: 2 affected family members have the variant from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and 1 affected family member has the variant (PMID: 35222550), so PP1 is met.

PM3

Variant meets PM2 and is identified in 1 index case with homozygous FH phenotype (LDL-C=11.7 mmol/L) and LDLR c. 2043C>T/p.(Cys681*), classified as Pathogenic by these guidelines, in trans, from Germany, so PM3 is met.

PM2

This variant is absent from gnomAD (gnomAD v4.1.0), so PM2 is Met.

BP2

BP4

REVEL = 0.713, it is not below 0.50, so BP4 is not met.

BP7

Variant is not synonymous, so BP7 is Not Met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

PVS1

Variant is missense, so PVS1 is Not Met.

PP3

REVEL = 0.713, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) does not create AG or GT C) no AG/GT nearby Variant is not predicted to alter splicing, so PP3 is Not Met.

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1916T>G (p.Val639Gly) (ClinVar ID 252112) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residue, so PM1 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

BA1

This variant is absent from gnomAD (gnomAD v4.1.0), so BA1 is not met.

BS2

Not detected in 100 normolipidemic individuals, so BS2 is not met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

This variant is absent from gnomAD (gnomAD v4.1.0), so BS1 is not met.

Curation History

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