Variant: NM_000527.5(LDLR):c.2041T>G (p.Cys681Gly)

CA10585740

252185 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 6ea22d66-0335-4bd2-9889-74e670390de4

Approved on: 2025-03-24

Published on: 2025-03-24

HGVS expressions

NM_000527.5:c.2041T>G
NM_000527.5(LDLR):c.2041T>G (p.Cys681Gly)
NC_000019.10:g.11120423T>G
CM000681.2:g.11120423T>G
NC_000019.9:g.11231099T>G
CM000681.1:g.11231099T>G
NC_000019.8:g.11092099T>G
NG_009060.1:g.36043T>G
ENST00000252444.10:c.2299T>G
ENST00000559340.2:c.*110T>G
ENST00000560467.2:c.1921T>G
ENST00000558518.6:c.2041T>G
ENST00000252444.9:c.2295T>G
ENST00000455727.6:c.1537T>G
ENST00000535915.5:c.1918T>G
ENST00000545707.5:c.1606+190T>G
ENST00000557933.5:c.2041T>G
ENST00000558013.5:c.2041T>G
ENST00000558518.5:c.2041T>G
NM_000527.4:c.2041T>G
NM_001195798.1:c.2041T>G
NM_001195799.1:c.1918T>G
NM_001195800.1:c.1537T>G
NM_001195803.1:c.1606+190T>G
NM_001195798.2:c.2041T>G
NM_001195799.2:c.1918T>G
NM_001195800.2:c.1537T>G
NM_001195803.2:c.1606+190T>G

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM1 PM2

• Not Met criteria codes: BA1 BP4 BS1 PM5 PS1

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.2041T>G (p.Cys681Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 24 March 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v.4.1.0). PM1: Variant meets PM2 and alters Cys681, one of the cysteine residues listed. PP3: REVEL = 0.957. PP4: Variant meets PM2 and is identified in 1 case with DLCN score >=6 in PMID 18648394 (Snozek et al., 2009), after alternative causes of high cholesterol were excluded.

Met criteria codes

• PP4: Variant meets PM2. Identified in 1 FH case (PMID: 18648394) with DLCN ≥ 6, after alternative causes of high cholesterol were excluded. Note, variant is in cis with LDLR c.-217C>T, which has been classified as benign by the VCEP.
• PP3: REVEL = 0.957, above 0.75
• PM1: Variant meets PM2 and alters Cys681, one of the cysteine residues listed.
• PM2: This variant is absent from gnomAD (gnomAD v4.1.0)

Not Met criteria codes

• BA1: This variant is absent from gnomAD (gnomAD v4.1.0)
• BP4: REVEL = 0.957, above 0.75
• BS1: This variant is absent from gnomAD (gnomAD v4.1.0)
• PM5: Variant meets PM1 and 1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2041T>A (p.Cys681Ser) (ClinVar ID 252184) - Conflicting evidence of pathogenicity by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PS1: Variant meets PM1 and 1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2041T>A (p.Cys681Ser) (ClinVar ID 252184) - Conflicting evidence of pathogenicity by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.