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]
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Variant: NM_000527.5(LDLR):c.2374A>T (p.Ile792Phe)

CA10585833

252294 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: bc00da18-8b21-473f-8be6-72a4adf4a5d0

HGVS expressions

NM_000527.5:c.2374A>T
NM_000527.5(LDLR):c.2374A>T (p.Ile792Phe)
NC_000019.10:g.11128070A>T
CM000681.2:g.11128070A>T
NC_000019.9:g.11238746A>T
CM000681.1:g.11238746A>T
NC_000019.8:g.11099746A>T
NG_009060.1:g.43690A>T
ENST00000558518.6:c.2374A>T
ENST00000252444.9:n.2628A>T
ENST00000455727.6:c.1870A>T
ENST00000535915.5:c.2251A>T
ENST00000545707.5:c.1840A>T
ENST00000557933.5:c.2374A>T
ENST00000558013.5:c.2374A>T
ENST00000558518.5:c.2374A>T
ENST00000560628.1:n.108+416A>T
NM_000527.4:c.2374A>T
NM_001195798.1:c.2374A>T
NM_001195799.1:c.2251A>T
NM_001195800.1:c.1870A>T
NM_001195803.1:c.1840A>T
NM_001195798.2:c.2374A>T
NM_001195799.2:c.2251A>T
NM_001195800.2:c.1870A>T
NM_001195803.2:c.1840A>T

Uncertain Significance

Met criteria codes 2
PP3 PM2
Not Met criteria codes 2
PS3 PM5

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.2374A>T (p. Ile792Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.764. PS3_Moderate not met: Level 2 experiment, heterologous cells (HepG2) were used for western blot and immunoprecipitation assays showed normal cell surface LDLR, reported by Strøm et al, 2015, (PMID 26220972), Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics and Department of Microbiology and Bioinformatics Core Facility, University of Oslo and Oslo University Hospital, Oslo, Norway. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2375T>C (p.Ile792Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
Met criteria codes
PP3
REVEL = 0.764.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PS3
Level 2 experiment, heterologous cells (HepG2) were used for western blot and immunoprecipitation assays showed normal cell surface LDLR, reported by Strøm et al, 2015, (PMID 26220972), Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics and Department of Microbiology and Bioinformatics Core Facility, University of Oslo and Oslo University Hospital, Oslo, Norway.
PM5
There is one other variant in the same codon: LDLR: NM_000527:c.2375T>C (p.Ile792Thr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
Approved on: 2022-08-26
Published on: 2022-12-23
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