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.1448G>T (p.Trp483Leu)

CA404086098

440645 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: b168d44c-5e10-4880-9fcd-f2890b71fca9

HGVS expressions

NM_000527.5:c.1448G>T
NM_000527.5(LDLR):c.1448G>T (p.Trp483Leu)
NC_000019.10:g.11113624G>T
CM000681.2:g.11113624G>T
NC_000019.9:g.11224300G>T
CM000681.1:g.11224300G>T
NC_000019.8:g.11085300G>T
NG_009060.1:g.29244G>T
ENST00000558518.6:c.1448G>T
ENST00000252444.9:n.1702G>T
ENST00000455727.6:c.944G>T
ENST00000535915.5:c.1325G>T
ENST00000545707.5:c.1067G>T
ENST00000557933.5:c.1448G>T
ENST00000558013.5:c.1448G>T
ENST00000558518.5:c.1448G>T
ENST00000559340.1:n.169G>T
ENST00000560467.1:n.928G>T
NM_000527.4:c.1448G>T
NM_001195798.1:c.1448G>T
NM_001195799.1:c.1325G>T
NM_001195800.1:c.944G>T
NM_001195803.1:c.1067G>T
NM_001195798.2:c.1448G>T
NM_001195799.2:c.1325G>T
NM_001195800.2:c.944G>T
NM_001195803.2:c.1067G>T

Uncertain Significance

Met criteria codes 2
PM2 PP3
Not Met criteria codes 20
PS1 PS2 PS4 PS3 PM6 PM3 PM4 PM5 PM1 BA1 PVS1 BP7 BP2 BP4 BS4 BS3 BS1 BS2 PP1 PP4

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1448G>T (p.Trp483Leu) 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), so PM2 is Met. PP3 - REVEL = 0.933. It is above 0.75, so PP3 is Met.
Met criteria codes
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.
PP3
REVEL = 0.933. It is above 0.75, so PP3 is Met.
Not Met criteria codes
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.
PS4
Variant meets PM2 but phenotype data is not reported, so PP4 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.
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.1449G>T (p.Trp483Cys) (ClinVar ID 251850) - VUS by these guidelines - NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) (ClinVar ID 251847) - VUS by these guidelines - NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys) (ClinVar ID 440646) - VUS by these guidelines There are no more variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.
PM1
Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
BA1
This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.
PVS1
Variant is missense, so PVS1 is Not 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 = 0.933. It is not below 0.50, so BP4 is Not Met.
BS4
Lack of segregation data not reported, so BS4 is Not Met.
BS3
There are no functional studies reported for this variant, so BS3 is not met.
BS1
This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.
BS2
No control individuals tested, so BS2 is Not Met.
PP1
Segregation data not reported, so PP1 is Not Met.
PP4
Variant meets PM2 but phenotype data is not reported, so PP4 is Not Met.
Approved on: 2023-04-29
Published on: 2023-04-29
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