Evidence Repository
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 computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala)

CA404093326

810849 (ClinVar)

Gene: LDLR (HGNC:3949)
Condition: hypercholesterolemia, familial (MONDO:0007750)
Inheritance Mode: Semidominant inheritance
UUID: 0eee2ad7-300d-4df6-80b5-12ff2b1d6e7c
Approved on: 2023-06-23
Published on: 2025-09-15

HGVS expressions

NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala)
NM_000527.5:c.1981C>G
NC_000019.10:g.11120227C>G
CM000681.2:g.11120227C>G
NC_000019.9:g.11230903C>G
CM000681.1:g.11230903C>G
NC_000019.8:g.11091903C>G
NG_009060.1:g.35847C>G
ENST00000252444.10:c.2239C>G
ENST00000559340.2:c.*50C>G
ENST00000560467.2:c.1861C>G
ENST00000558518.6:c.1981C>G
ENST00000252444.9:c.2235C>G
ENST00000455727.6:c.1477C>G
ENST00000535915.5:c.1858C>G
ENST00000545707.5:c.1600C>G
ENST00000557933.5:c.1981C>G
ENST00000558013.5:c.1981C>G
ENST00000558518.5:c.1981C>G
ENST00000559340.1:c.562C>G
NM_000527.4:c.1981C>G
NM_001195798.1:c.1981C>G
NM_001195799.1:c.1858C>G
NM_001195800.1:c.1477C>G
NM_001195803.1:c.1600C>G
NM_001195798.2:c.1981C>G
NM_001195799.2:c.1858C>G
NM_001195800.2:c.1477C>G
NM_001195803.2:c.1600C>G
More

Likely Pathogenic

Met criteria codes 3
PM2 PS3 PP4
Not Met criteria codes 23
PM3 PM1 PM4 PM5 PM6 BS4 BS3 BS1 BS2 PVS1 PS2 PS4 PS1 BP5 BP7 BP4 BP1 BP2 BP3 BA1 PP3 PP2 PP1

Evidence Links 0

Expert Panel

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.1981C>G (p.Pro661Ala) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2 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). PS3: Level 1 assays: PMID 31689621 (Gomez et al., 2019): Heterologous cells (CHO-ldlA7), RT qPCR and 125I-LDL assays - results – normal (100%) LDLR expression and 50% uptake and catabolism -> results are below 70% of wild-type, so functional study is consistent with damaging effect. PP4: Variant meets PM2 and is identified in 1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon (France) with DLCN score ≥ 6, after alternative causes of high cholesterol were excluded.
Met criteria codes
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
PS3
Level 1 assays: PMID: 31689621: Heterologous cells (CHO-ldlA7), RT qPCR and 125I-LDL assays - results – normal (100%) LDLR expression and 50% uptake and catabolism ---- results are below 70% of wild-type, so functional study is consistent with damaging effect.
PP4
Variant meets PM2. Identified in 1 FH case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon (France) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6, after alternative causes of high cholesterol were excluded.
Not Met criteria codes
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1982C>T (p.Pro661Leu) (ClinVar ID 375827) - Uncertain significance - insufficient evidence by these guidelines - NM_000527.5(LDLR):c.1981C>A (p.Pro661Thr) (ClinVar ID 441225) - Uncertain significance - insufficient evidence by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL = 0.639, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. Scenario A, Acceptor site: The variant is NOT located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is NOT located at -3 to +6 bases of canonical splicing site of any exons. Scenario B, Acceptor site: The variant is NOT located within the range and DOES NOT create de novo AG site. Scenario B, Donor site: The variant is located within range and DOES NOT create de novo GT site. Scenario C, Acceptor site: The variant is NOT located at -20 to +3 bases of intraexonic AG. Scenario C, Donor site: The variant is NOT located at -3 to +6 bases of intraexonic GT. Interpretation: The variant DOES NOT affect splicing
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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