The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn)

CA023502

161284 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: 80bb5f03-87c5-45e6-9b97-a70014c29afa
Approved on: 2023-06-23
Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1444G>A
NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn)
NC_000019.10:g.11113620G>A
CM000681.2:g.11113620G>A
NC_000019.9:g.11224296G>A
CM000681.1:g.11224296G>A
NC_000019.8:g.11085296G>A
NG_009060.1:g.29240G>A
ENST00000252444.10:c.1702G>A
ENST00000559340.2:c.1444G>A
ENST00000560467.2:c.1324G>A
ENST00000558518.6:c.1444G>A
ENST00000252444.9:c.1698G>A
ENST00000455727.6:c.940G>A
ENST00000535915.5:c.1321G>A
ENST00000545707.5:c.1063G>A
ENST00000557933.5:c.1444G>A
ENST00000558013.5:c.1444G>A
ENST00000558518.5:c.1444G>A
ENST00000559340.1:c.165G>A
ENST00000560467.1:c.924G>A
NM_000527.4:c.1444G>A
NM_001195798.1:c.1444G>A
NM_001195799.1:c.1321G>A
NM_001195800.1:c.940G>A
NM_001195803.1:c.1063G>A
NM_001195798.2:c.1444G>A
NM_001195799.2:c.1321G>A
NM_001195800.2:c.940G>A
NM_001195803.2:c.1063G>A
More

Pathogenic

Met criteria codes 5
PP1_Strong PS4 PM2 PP4 PP3
Not Met criteria codes 16
BP2 BP3 BP4 PS1 PS2 PS3 BA1 PVS1 PM6 PM5 PM3 PM1 PM4 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, 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: PopMax MAF = 0.00009 (0.009%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.945. PS4, PP4: Variant meets PM2 and is identified in at least 14 unrelated index cases who fulfill criteria for FH (3 cases with Simon-Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 3 cases with DLCN score >=6 and 1 case with Simon-Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 3 cases with DLCN score >=6 from Robarts Research Institute, Canada; 3 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; 1 case with DLCN score>=6 from Color Health, Inc, USA). PP1_Strong: Variant segregates with FH phenotype in at least 11 informative meioses in 4 families from different labs (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 8 affected family members have the variant and 3 unaffected family members do not have the variant.
Met criteria codes
PP1_Strong
Variant segregates with FH phenotype in 11 informative meioses in 4 families from different labs (Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 8 affected family members have the variant and 3 non-affected family members do not have the variant. So, PP1_Strong is met.
PS4
Variant meets PM2 and is identified in 14 unrelated cases (3 cases with Simon-Broome criteria of FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria and 1 case with Simon-Broome criteria of FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 3 cases with DLCN criteria of FH from Robarts Research Institute; 3 cases with DLCN criteria of FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with DLCN criteria of FH from Color Health, Inc). So, PS4 is met.
PM2
PopMax MAF = 0.00009 (0.009%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So, PM2 is met.
PP4
Variant meets PM2 and is identified in 14 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded.
PP3
REVEL=0.945. It is above 0.75, so PP3 is met.
Not Met criteria codes
BP2
No data available
BP3
No in-frame deletions/insertions
BP4
REVEL=0.945.
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 data available
BA1
PopMax MAF = 0.00009 (0.009%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).
PVS1
Not a null variant
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
3 other missense variants in the same codon: - 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 - NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) (ClinVar ID 251846) - Likely Pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM3
No data available
PM1
Not in exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No data available
BS1
PopMax MAF = 0.00009 (0.009%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).
Curation History
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