Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1196C>A (p.Ala399Asp)

CA10576301

226350 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: b81fb118-4d2b-4441-8fe1-db5668f18578

Approved on: 2026-01-23

Published on: 2026-01-28

HGVS expressions

NM_000527.5(LDLR):c.1196C>A (p.Ala399Asp)

NM_000527.5:c.1196C>A

NC_000019.10:g.11113287C>A

CM000681.2:g.11113287C>A

NC_000019.9:g.11223963C>A

CM000681.1:g.11223963C>A

NC_000019.8:g.11084963C>A

NG_009060.1:g.28907C>A

ENST00000252444.10:c.1454C>A

ENST00000559340.2:c.1196C>A

ENST00000560467.2:c.1076C>A

ENST00000558518.6:c.1196C>A

ENST00000252444.9:c.1450C>A

ENST00000455727.6:c.692C>A

ENST00000535915.5:c.1073C>A

ENST00000545707.5:c.815C>A

ENST00000557933.5:c.1196C>A

ENST00000558013.5:c.1196C>A

ENST00000558518.5:c.1196C>A

ENST00000560173.1:n.195C>A

ENST00000560467.1:c.676C>A

NM_000527.4:c.1196C>A

NM_001195798.1:c.1196C>A

NM_001195799.1:c.1073C>A

NM_001195800.1:c.692C>A

NM_001195803.1:c.815C>A

NM_001195798.2:c.1196C>A

NM_001195799.2:c.1073C>A

NM_001195800.2:c.692C>A

NM_001195803.2:c.815C>A

Likely Pathogenic

PP1_Strong PP3 PP4 PM2 PS4_Supporting

BP7 BP2 BP4 PS1 PS2 PS3 PM6 PM1 PM3 PM4 PM5 PVS1 BA1 BS2 BS4 BS1 BS3

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1196C>A (p.Ala399Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PS4_Supporting, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 23, 2026. The supporting evidence is as follows: PM2: PopMax MAF = 0.000003390 (0.0003390%) in European non-Finnish exomes+genomes (gnomAD v4.1). PP3: REVEL = 0.82. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH from different labs (2 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; at least 1 case with DLCN score >=6 from PMID 11810272 (Fouchier et al., 2001), The Netherlands). PP1_Strong - Variant segregates with FH phenotype in at least 6 informative meioses (minimum 6) from 2 families from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia: 5 affected family members have the variant and 1 non-affected family member does not have the variant.

PP1_Strong

Variant segregates with FH phenotype in at least 6 informative meioses (minimum 6) from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 5 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1_Strong is met.

PP3

REVEL = 0.82. It is above 0.75, so PP3 is met.

PP4

Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH from different labs (2 unrelated index cases, both with Dutch lipid clinic network >=6; at least 1 index case who fulfills DLCN>9 criteria for FH (definite FH) from The Netherlands (PMID: 11810272)), after alternative causes of high cholesterol were excluded so PP4 is met.

PM2

PopMax MAF = 0.000003390 (0.0003390%) in European non Finnish exomes+genomes (gnomAD v4.1), so PM2 is Met.

PS4_Supporting

Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH from different labs (2 unrelated index cases, both with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); at least 1 index case who fulfills DLCN>9 criteria for FH (definite FH) from The Netherlands (PMID: 11810272)), so PS4_Supporting is Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Not observed in trans with other LP/P variants, so BP2 is Not Met.

BP4

REVEL = 0.82. It is not below 0.50, so BP4 is Not Met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residue, so PM1 is Not Met.

PM3

Not observed in trans with other LP/P variants, so PM3 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM5

3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1195G>A (p.Ala399Thr) (ClinVar ID 183109) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1195G>T (p.Ala399Ser) (ClinVar ID 440632) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1196C>T (p.Ala399Val) (ClinVar ID 3074081) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.

PVS1

Variant is missense, so PVS1 is Not Met.

BA1

PopMax MAF = 0.000003390 (0.0003390%) in European non Finnish exomes+genomes (gnomAD v4.1), so BA1 is not Met.

BS2

Case-control data not reported, so BS2 is Not Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS1

PopMax MAF = 0.000003390 (0.0003390%) in European non Finnish exomes+genomes (gnomAD v4.1), so BS1 is not Met.

BS3

There are no functional studies reported for this variant, so BS3 is Not Met.

Curation History

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