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 related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.1367T>A (p.Leu456His)

CA10585429

251817 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: 0838ddbd-012c-464a-9a2d-08b10f9e7471
Approved on: 2023-06-23
Published on: 2024-10-02

HGVS expressions

NM_000527.5:c.1367T>A
NM_000527.5(LDLR):c.1367T>A (p.Leu456His)
NC_000019.10:g.11113543T>A
CM000681.2:g.11113543T>A
NC_000019.9:g.11224219T>A
CM000681.1:g.11224219T>A
NC_000019.8:g.11085219T>A
NG_009060.1:g.29163T>A
ENST00000252444.10:c.1625T>A
ENST00000559340.2:c.1367T>A
ENST00000560467.2:c.1247T>A
ENST00000558518.6:c.1367T>A
ENST00000252444.9:c.1621T>A
ENST00000455727.6:c.863T>A
ENST00000535915.5:c.1244T>A
ENST00000545707.5:c.986T>A
ENST00000557933.5:c.1367T>A
ENST00000558013.5:c.1367T>A
ENST00000558518.5:c.1367T>A
ENST00000559340.1:c.88T>A
ENST00000560467.1:c.847T>A
NM_000527.4:c.1367T>A
NM_001195798.1:c.1367T>A
NM_001195799.1:c.1244T>A
NM_001195800.1:c.863T>A
NM_001195803.1:c.986T>A
NM_001195798.2:c.1367T>A
NM_001195799.2:c.1244T>A
NM_001195800.2:c.863T>A
NM_001195803.2:c.986T>A
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Uncertain Significance

Met criteria codes 4
PP1 PP4 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.1367T>A (p.Leu456His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PP1 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: Variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.856. PP4: Variant meets PM2 and is identified in 1 index case who fulfills criteria for FH after alternative causes of high cholesterol were excluded (PMID 16542394, Brusgaard et al., 2006, Denmark). PP1: Variant segregates with FH phenotype in at least 2 informative meioses from 1 family (PMID 16542394, Brusgaard et al., 2006, Denmark): 2 affected family members have the variant.
Met criteria codes
PP1
In PMID 16542394, variant segregates with FH phenotype in at least two relatives with LDLC >75th percentile in one family (shown in Table 1 and Table 2), by Brusgaard et al, 2006.
PP4
Variant meets PM2 and is identified in 1 index case who fulfil two of three criteria: LDL>6 mmol/l, presence of tendon xanthoma, CAD before age of 60 yrs or family history of CAD, after alternative causes of high cholesterol were excluded, reported in PMID 16542394 by Brusgaard et al, 2006, from Odense University, Denmark.
PP3
REVEL=0.856, it is above the impact threshold of 0.75.
PM2
Variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PS3
Functional data is not available.
PM5
Two other variants at same codon: LDLR:c.1367T>C (p.Leu456Pro) classified as VUS; LDLR:c.1366C>T(p. Leu456Phe) classified as VUS by these guidelines, therefore PM5 is not met.
Curation History
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