Variant: NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly)

CA10585456

251846 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 454940dc-2ff7-4f33-b60c-2ce9595fe8cb

Approved on: 2023-06-23

Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1445A>G
NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly)
NC_000019.10:g.11113621A>G
CM000681.2:g.11113621A>G
NC_000019.9:g.11224297A>G
CM000681.1:g.11224297A>G
NC_000019.8:g.11085297A>G
NG_009060.1:g.29241A>G
ENST00000252444.10:c.1703A>G
ENST00000559340.2:c.1445A>G
ENST00000560467.2:c.1325A>G
ENST00000558518.6:c.1445A>G
ENST00000252444.9:c.1699A>G
ENST00000455727.6:c.941A>G
ENST00000535915.5:c.1322A>G
ENST00000545707.5:c.1064A>G
ENST00000557933.5:c.1445A>G
ENST00000558013.5:c.1445A>G
ENST00000558518.5:c.1445A>G
ENST00000559340.1:c.166A>G
ENST00000560467.1:c.925A>G
NM_000527.4:c.1445A>G
NM_001195798.1:c.1445A>G
NM_001195799.1:c.1322A>G
NM_001195800.1:c.941A>G
NM_001195803.1:c.1064A>G
NM_001195798.2:c.1445A>G
NM_001195799.2:c.1322A>G
NM_001195800.2:c.941A>G
NM_001195803.2:c.1064A>G

Likely Pathogenic

• Met criteria codes: PM2 PM5 PP3 PP4

• Not Met criteria codes: BS1 BS4 BS3 BS2 BP4 BP3 BP2 PM6 PM1 PM3 PM4 PS1 PS2 PS3 PS4 BA1 PP1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.987. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines; - NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines; - NM_000527.5(LDLR):c.1444G>C (p.Asp482His) (ClinVar ID 251844) - Likely Pathogenic by these guidelines; There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 index case who fulfills WHO criteria for FH from PMID 20145306 (Chmara M et al., 2010), after alternative causes of high cholesterol were excluded.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.
• PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1444G>C (p.Asp482His) (ClinVar ID 251844) - Likely Pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.
• PP3: REVEL=0.987. It is above 0.75, so PP3 is met.
• PP4: Variant meets PM2 and is identified in 1 index case who fulfills WHO criteria for FH from PMID 20145306, after alternative causes of high cholesterol were excluded.

Not Met criteria codes

• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BS4: No evidence available
• BS3: No evidence available
• BS2: No evidence available
• BP4: REVEL=0.987.
• BP3: No in-frame deletions/insertions
• BP2: No evidence available
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Not in exon 4. Not a cysteine residue.
• PM3: No evidence available
• PM4: No in-frame deletions/insertions
• PS1: No other missense variant in the same codon with the same amino acid change.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No evidence available
• PS4: No evidence available
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• PP1: No evidence available