Variant: NM_000527.5(LDLR):c.299A>G (p.Asp100Gly)

CA10584833

251122 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 03c25063-80f5-4f37-9ff5-f29833f5b7e7

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.299A>G
NM_000527.5(LDLR):c.299A>G (p.Asp100Gly)
NC_000019.10:g.11102772A>G
CM000681.2:g.11102772A>G
NC_000019.9:g.11213448A>G
CM000681.1:g.11213448A>G
NC_000019.8:g.11074448A>G
NG_009060.1:g.18392A>G
ENST00000558518.6:c.299A>G
ENST00000252444.9:n.553A>G
ENST00000455727.6:c.299A>G
ENST00000535915.5:c.190+2427A>G
ENST00000545707.5:c.299A>G
ENST00000557933.5:c.299A>G
ENST00000557958.1:n.385A>G
ENST00000558013.5:c.299A>G
ENST00000558518.5:c.299A>G
NM_000527.4:c.299A>G
NM_001195798.1:c.299A>G
NM_001195799.1:c.190+2427A>G
NM_001195800.1:c.299A>G
NM_001195803.1:c.299A>G
NM_001195798.2:c.299A>G
NM_001195799.2:c.190+2427A>G
NM_001195800.2:c.299A>G
NM_001195803.2:c.299A>G

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PP4 PP1 PP3 PM2 PS4_Supporting

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.299A>G (p.Asp100Gly) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PP4, PS4_supporting 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: This variant is absent from gnomAD (gnomAD v2.1.1). - PP1: variant segregates with FH phenotype in 3 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology: 2 relatives with the phenotype and the variant and 1 relative without the phenotype and without the variant. - PP3: REVEL = 0.9. - PP4: Variant meets PM2 and is identified in at least 1 index case (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH), after alternative causes of high cholesterol were excluded. - PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH)

Met criteria codes

• PP4: Variant meets PM2 and is identified in at least 1 index case (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH), after alternative causes of high cholesterol were excluded.
• PP1: variant segregates with FH phenotype in 3 informative meiosis in 1 family from Laboratory of Genetics and Molecular Cardiology: 2 relatives with the phenotype and the variant and 1 relative without the phenotype and without the variant.
• PP3: REVEL = 0.9.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1).
• PS4_Supporting: Variant meets PM2 and is identified in 2 index cases (1 index case from Laboratory of Genetics and Molecular Cardiology with Simon-Broome criteria of possible FH, 1 index case from PMID: 11810272 clinically diagnosed with definite heterozygous FH)