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 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.1366C>T (p.Leu456Phe)

CA034017

926526 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 1d551fc0-d415-4840-99f9-66e331949130
Approved on: 2023-06-23
Published on: 2024-10-02

HGVS expressions

NM_000527.5:c.1366C>T
NM_000527.5(LDLR):c.1366C>T (p.Leu456Phe)
NC_000019.10:g.11113542C>T
CM000681.2:g.11113542C>T
NC_000019.9:g.11224218C>T
CM000681.1:g.11224218C>T
NC_000019.8:g.11085218C>T
NG_009060.1:g.29162C>T
ENST00000252444.10:c.1624C>T
ENST00000559340.2:c.1366C>T
ENST00000560467.2:c.1246C>T
ENST00000558518.6:c.1366C>T
ENST00000252444.9:c.1620C>T
ENST00000455727.6:c.862C>T
ENST00000535915.5:c.1243C>T
ENST00000545707.5:c.985C>T
ENST00000557933.5:c.1366C>T
ENST00000558013.5:c.1366C>T
ENST00000558518.5:c.1366C>T
ENST00000559340.1:c.87C>T
ENST00000560467.1:c.846C>T
NM_000527.4:c.1366C>T
NM_001195798.1:c.1366C>T
NM_001195799.1:c.1243C>T
NM_001195800.1:c.862C>T
NM_001195803.1:c.985C>T
NM_001195798.2:c.1366C>T
NM_001195799.2:c.1243C>T
NM_001195800.2:c.862C>T
NM_001195803.2:c.985C>T
More

Uncertain Significance

Met criteria codes 2
BP4 PM2
Not Met criteria codes 3
PS4 PP4 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. 1366C>T (p. Leu456Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 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: PopMax MAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1). BP4: REVEL=0.487, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. MES performed: A) Variant is not on limits. B) Variant is on limit but does not crate de novo AG. Variant created GT however is not on limit. C) Variant is on limit and nearby three intra-exonic AGs: cctcctgcctcagcacccAGc/ttt , Var/Wt cryptic score = 0.37/-0.2 = -0.15, it is <1.1; ctcagcacccagc/tttgacAGagc, Var/Wt cryptic score = -3.2/-2.9 = 1.103, it is = 1.1, however both scores are negative; and agcacccagc/tttgacagAGccc, Var/Wt cryptic score = -33.4/-34.48 = 0.97, it is <1.1. MES score for canonical intron 9 acceptor cttctctcctcctgcctcAGcac is 6.76, so none of the Var cryptic scores/Wt score is >0.9. Variant is not predicted to alter splicing and REVEL score is below 0.5, therefore BP4 is met.
Met criteria codes
BP4
REVEL=0.487, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. MES performed: A) Variant is not on limits. B) Variant is on limit but does not crate de novo AG. Variant created GT however is not on limit. C) Variant is on limit and nearby three intra-exonic AGs: cctcctgcctcagcacccAGc/ttt , Var/Wt cryptic score = 0.37/-0.2 = -0.15, it is <1.1; ctcagcacccagc/tttgacAGagc, Var/Wt cryptic score = -3.2/-2.9 = 1.103, it is = 1.1, however both scores are negative; and agcacccagc/tttgacagAGccc, Var/Wt cryptic score = -33.4/-34.48 = 0.97, it is <1.1. MES score for canonical intron 9 acceptor cttctctcctcctgcctcAGcac is 6.76, so none of the Var cryptic scores/Wt score is >0.9. Variant is not predicted to alter splicing. REVEL score is below 0.5, therefore BP4 is met. SpliceAI confirmed same result.
PM2
PopMax MAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PS4
Clinical data is not available.
PP4
Clinical data is not available.
PM5
Two other variants at same codon: LDLR:c.1367T>C (p.Leu456Pro) classified as VUS; LDLR:c.1367T>A(p.Leu456His) classified as VUS by these guidelines, therefore PM5 is not met.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.