Variant: NM_000527.5(LDLR):c.1211C>T (p.Thr404Ile)

CA10585360

251736 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 0b713e51-bded-4ddb-a945-894590270b8f

Approved on: 2022-10-28

Published on: 2024-12-09

HGVS expressions

NM_000527.5:c.1211C>T
NM_000527.5(LDLR):c.1211C>T (p.Thr404Ile)
NC_000019.10:g.11113302C>T
CM000681.2:g.11113302C>T
NC_000019.9:g.11223978C>T
CM000681.1:g.11223978C>T
NC_000019.8:g.11084978C>T
NG_009060.1:g.28922C>T
ENST00000252444.10:c.1469C>T
ENST00000559340.2:c.1211C>T
ENST00000560467.2:c.1091C>T
ENST00000558518.6:c.1211C>T
ENST00000252444.9:c.1465C>T
ENST00000455727.6:c.707C>T
ENST00000535915.5:c.1088C>T
ENST00000545707.5:c.830C>T
ENST00000557933.5:c.1211C>T
ENST00000558013.5:c.1211C>T
ENST00000558518.5:c.1211C>T
ENST00000560173.1:n.210C>T
ENST00000560467.1:c.691C>T
NM_000527.4:c.1211C>T
NM_001195798.1:c.1211C>T
NM_001195799.1:c.1088C>T
NM_001195800.1:c.707C>T
NM_001195803.1:c.830C>T
NM_001195798.2:c.1211C>T
NM_001195799.2:c.1088C>T
NM_001195800.2:c.707C>T
NM_001195803.2:c.830C>T

Likely Pathogenic

• Met criteria codes: PM3 PM2 PS4_Supporting PP4 PP3

• Not Met criteria codes: PM1 PM4 PM5 PM6 PVS1 BA1 BS4 BS3 BS1 BS2 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP1 PP2

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.1211C>T (p.Thr404Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2022. The supporting evidence is as follows: PM2: This variant is absent from gnomAD v2.1.1. PP3: REVEL = 0.928. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill criteria for FH after alternative causes of high cholesterol were excluded (1 case with DLCN score >=6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, Italy; 1 case from PMID 19446849). PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype and LDLR variant (c.428G>A (p.Cys143Tyr)) classified as Pathogenic by these guidelines, in trans (PMID 14570618, 19073363).

Met criteria codes

• PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype and LDLR variant (c.428G>A (p.Cys143Tyr)), classified as Pathogenic by these guidelines, in trans, from PMID:14570618 and PMID:19073363.
• PM2: This variant is absent from gnomAD v2.1.1
• PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill SB possible/definite FH/DLCN>=6 criteria for FH from PMID 28965616, 23375686, 19446849, 19073363, and the Research Lab of Molecular Genetics of Lipid Metabolism.
• PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible/definite FH/DLCN>=6 criteria for FH from PMID 28965616, 23375686, 19446849, 19073363 and the Research Lab of Molecular Genetics of Lipid Metabolism, after alternative causes of high cholesterol were excluded.
• PP3: REVEL = 0.928

Not Met criteria codes

• PM1: Not located in exon 4 or at a cysteine residue.
• PM4: Not an in-frame deletion or insertion.
• PM5: Not met.
• PM6: Not met.
• PVS1: Not met.
• BA1: This variant is absent from gnomAD v2.1.1
• BS4: Not met.
• BS3: Not met.
• BS1: This variant is absent from gnomAD v2.1.1
• BS2: Not met.
• BP7: Not a synonymous variant.
• BP2: Not met.
• BP3: Not applicable
• BP4: REVEL = 0.928
• BP1: Not applicable
• PS2: Not met.
• PS3: Not met.
• PS1: Not met.
• PP1: Not met.
• PP2: Not applicable