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.1840T>A (p.Phe614Ile)

CA10585641

252061 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: c4198a80-aa3c-47c4-8d4a-cf47af9816b9
Approved on: 2025-03-28
Published on: 2025-06-30

HGVS expressions

NM_000527.5:c.1840T>A
NM_000527.5(LDLR):c.1840T>A (p.Phe614Ile)
NC_000019.10:g.11116993T>A
CM000681.2:g.11116993T>A
NC_000019.9:g.11227669T>A
CM000681.1:g.11227669T>A
NC_000019.8:g.11088669T>A
NG_009060.1:g.32613T>A
ENST00000252444.10:c.2098T>A
ENST00000559340.2:c.1705+781T>A
ENST00000560467.2:c.1720T>A
ENST00000558518.6:c.1840T>A
ENST00000252444.9:c.2094T>A
ENST00000455727.6:c.1336T>A
ENST00000535915.5:c.1717T>A
ENST00000545707.5:c.1459T>A
ENST00000557933.5:c.1840T>A
ENST00000558013.5:c.1840T>A
ENST00000558518.5:c.1840T>A
ENST00000559340.1:c.426+781T>A
NM_000527.4:c.1840T>A
NM_001195798.1:c.1840T>A
NM_001195799.1:c.1717T>A
NM_001195800.1:c.1336T>A
NM_001195803.1:c.1459T>A
NM_001195798.2:c.1840T>A
NM_001195799.2:c.1717T>A
NM_001195800.2:c.1336T>A
NM_001195803.2:c.1459T>A
More

Likely Pathogenic

Met criteria codes 5
PM2 PS3 PP1 PP4 PP3
Not Met criteria codes 16
PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS1 BP2 BP3 BP4 BP7 BA1 PS2 PS4 PS1

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.1840T>A (p.Phe614Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 March 2025.. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL=0.912. PS3: Level 1 assays: PMID 35568682 (Graça et al., 2022): Heterologous cells (CHO-ldlA7 cells), cytometry assays - results - <60% surface LDLR, <60% LDL-LDLR binding, <60% uptake. ---- 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 with Possible FH by Simon Broome criteria from Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Cardiovascular Research group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal.
Met criteria codes
PM2
This variant is absent from gnomAD (gnomAD v4.1.0). So, PM2 is met.
PS3
Level 1 assays: PMID 35568682: Heterologous cells (CHO-ldlA7 cells), cytometry assays - results - <60% surface LDLR, <60% LDL-LDLR binding, <60% uptake. ---- results are below 70% of wild-type, so functional study is consistent with damaging effect. PS3 is met.
PP1
Variant segregates with FH phenotype in 2 informative meioses identified by Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge. So, PP1 is met.
PP4
Variant meets PM2. Identified in 1 FH case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon Broome criteria of possible FH, after alternative causes of high cholesterol were excluded. So, PP4 is met.
PP3
REVEL=0.912. It is above 0.75, so PP3 is met.
Not Met criteria codes
PM3
No data available.
PM1
Not on exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions.
PM5
No other missense variant in the same codon.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No data available.
BS4
No data available.
BS1
This variant is absent from gnomAD (gnomAD v4.1.0).
BP2
No data available.
BP3
No in-frame deletions/insertions.
BP4
REVEL=0.912. It is above 0.5.
BP7
Not a synonymous variant.
BA1
This variant is absent from gnomAD (gnomAD v4.1.0).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant meets PM2. Identified in 1 FH case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon Broome criteria of possible FH, after alternative causes of high cholesterol were excluded.
PS1
No other missense variant in the same codon.
Curation History
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