Variant: NM_000527.5(LDLR):c.510C>A (p.Asp170Glu)

CA16609804

403662 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 64d0b8e1-535a-413f-b7d4-5d7c305a9aa6

Approved on: 2025-03-09

Published on: 2025-03-09

HGVS expressions

NM_000527.5:c.510C>A
NM_000527.5(LDLR):c.510C>A (p.Asp170Glu)
NC_000019.10:g.11105416C>A
CM000681.2:g.11105416C>A
NC_000019.9:g.11216092C>A
CM000681.1:g.11216092C>A
NC_000019.8:g.11077092C>A
NG_009060.1:g.21036C>A
ENST00000252444.10:c.768C>A
ENST00000559340.2:c.510C>A
ENST00000560467.2:c.510C>A
ENST00000558518.6:c.510C>A
ENST00000252444.9:c.764C>A
ENST00000455727.6:c.314-1976C>A
ENST00000535915.5:c.387C>A
ENST00000545707.5:c.314-1149C>A
ENST00000557933.5:c.510C>A
ENST00000558013.5:c.510C>A
ENST00000558518.5:c.510C>A
ENST00000560467.1:c.110C>A
NM_000527.4:c.510C>A
NM_001195798.1:c.510C>A
NM_001195799.1:c.387C>A
NM_001195800.1:c.314-1976C>A
NM_001195803.1:c.314-1149C>A
NM_001195798.2:c.510C>A
NM_001195799.2:c.387C>A
NM_001195800.2:c.314-1976C>A
NM_001195803.2:c.314-1149C>A

Likely Pathogenic

• Met criteria codes: PP4 PM1 PM2 PS4_Supporting

• Not Met criteria codes: BP4 PP3

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.510C>A (p.Asp170Glu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 9 March 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002664 (0.002664%) in African/African American exomes (gnomAD v4.1.0). PM1: Variant meets PM2 and is missense in exon 4. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill Simon Broome criteria for possible FH (1 case from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case meeting Simon Broome criteria for possible FH in PMID 27824480 (Gabčová et al., 2017)).

Met criteria codes

• PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible FH criteria after alternative causes of high cholesterol were excluded (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation).
• PM1: Variant meets PM2 and is missense in exon 4.
• PM2: PopMax MAF = 0.00002664 (0.002664%) in African/African American exomes (gnomAD v4.1.0).
• PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill SB possible criteria for FH. (1) 1 FH patient meeting SB possible criteria carries the variant (Molecular Genetics Laboratory ,Centre for Cardiovascular Surgery and Transplantation) (2) 1 FH patient meeting SB possible criteria carries the variant (PMID: 27824480)

Not Met criteria codes

• BP4: REVEL = 0.29. It is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) not on limits; B) does not create AG/GT; C) there is an AG nearby. MES scores: variant cryptic = -1.47, wt cryptic = -0.20, canonical donor = 8.16. Ratio variant cryptic/wt cryptic: -1.47/-0.20 = 7.35 --- it is above 1.1. Ratio variant cryptic/canonical donor: -1.47/8.16 = -0.18 --- it is not above 0.9. Variant is not predicted to alter splicing. PP3 is not met; BP4 is not met.
• PP3: REVEL = 0.29. It is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) not on limits; B) does not create AG/GT; C) there is an AG nearby. MES scores: variant cryptic = -1.47, wt cryptic = -0.20, canonical donor = 8.16. Ratio variant cryptic/wt cryptic: -1.47/-0.20 = 7.35 --- it is above 1.1. Ratio variant cryptic/canonical donor: -1.47/8.16 = -0.18 --- it is not above 0.9. Variant is not predicted to alter splicing. PP3 is not met; BP4 is not met.