Variant: NM_000527.5(LDLR):c.865T>C (p.Cys289Arg)

CA10585164

251492 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: e80e5038-aebf-4b46-9d96-2f64261b49a0

Approved on: 2025-01-31

Published on: 2025-02-27

HGVS expressions

NM_000527.5:c.865T>C
NM_000527.5(LDLR):c.865T>C (p.Cys289Arg)
NC_000019.10:g.11107439T>C
CM000681.2:g.11107439T>C
NC_000019.9:g.11218115T>C
CM000681.1:g.11218115T>C
NC_000019.8:g.11079115T>C
NG_009060.1:g.23059T>C
ENST00000252444.10:c.1123T>C
ENST00000559340.2:c.865T>C
ENST00000560467.2:c.865T>C
ENST00000558518.6:c.865T>C
ENST00000252444.9:c.1119T>C
ENST00000455727.6:c.361T>C
ENST00000535915.5:c.742T>C
ENST00000545707.5:c.484T>C
ENST00000557933.5:c.865T>C
ENST00000558013.5:c.865T>C
ENST00000558518.5:c.865T>C
ENST00000558528.1:n.380T>C
ENST00000560467.1:c.465T>C
NM_000527.4:c.865T>C
NM_001195798.1:c.865T>C
NM_001195799.1:c.742T>C
NM_001195800.1:c.361T>C
NM_001195803.1:c.484T>C
NM_001195798.2:c.865T>C
NM_001195799.2:c.742T>C
NM_001195800.2:c.361T>C
NM_001195803.2:c.484T>C

Likely Pathogenic

• Met criteria codes: PP4 PP3 PS4_Supporting PM2 PM1

• Not Met criteria codes: BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 BA1 PP1 PP2 PM6 PM3 PM4 PM5 PVS1 BS2 BS4 BS3 BS1

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.865T>C (p.Cys289Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM1 - Variant meets PM2 and alters Cys289, one of the cysteine residues listed; PM2 - This variant is absent from gnomAD (gnomAD v4.1.0); PP3 - REVEL = 0.933; PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded; PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case fulfilling Japanese Atherosclerosis Society criteria from PMID: 35929461 (Funabashi et al., 2022), Japan; 1 case fulfilling internationally accepted criteria for FH from PMID: 16314194 (Robles-Osorio et al., 2006), Mexico).

Met criteria codes

• PP4: Variant meets PM2 and is identified in 2 index cases who fulfill Japanese Atherosclerosis Society/other criteria for FH from PMID 35929461, 16314194, after alternative causes of high cholesterol were excluded.
• PP3: REVEL = 0.933
• PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases (1 case fulfilling Japanese Atherosclerosis Society criteria from PMID: 35929461 (Funabashi et al., 2022), Japan; 1 case fulfilling internationally accepted criteria for FH from PMID: 16314194 (Robles-Osorio et al., 2006), Mexico)
• PM2: This variant is absent from gnomAD (gnomAD v4.1.0)
• PM1: Variant meets PM2 and alters Cys289, one of the cysteine residues listed.

Not Met criteria codes

• BP2: Not identified in individuals with other variants.
• BP3: Not applicable.
• BP4: REVEL = 0.933. Score is not below 0.50.
• BP1: Not applicable.
• BP5: Not applicable.
• BP7: Missense variant. Not applicable.
• PS2: No de novo cases were identified.
• PS3: No functional assays performed/found - not applicable.
• PS1: Variant meets PM1, so not applicable.
• BA1: No population data was found for this allele in gnomAD (gnomAD v4.1.0).
• PP1: No segregations were identified/found.
• PP2: Not applicable.
• PM6: No de novo cases were identified.
• PM3: Not identified in individuals with other variants.
• PM4: Not applicable.
• PM5: Cannot apply PM5 as variant already meets PM1.
• PVS1: Missense variant. Not applicable.
• BS2: No unaffected individuals identified with the variant.
• BS4: No non-segregations were identified/found.
• BS3: No functional assays performed/found - not applicable.
• BS1: No population data was found for this allele in gnomAD (gnomAD v4.1.0).