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.1927G>C (p.Ala643Pro)

CA10585682

252114 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: 67ec196b-6313-43ac-a7da-0017f218f6af
Approved on: 2024-07-02
Published on: 2024-09-24

HGVS expressions

NM_000527.5:c.1927G>C
NM_000527.5(LDLR):c.1927G>C (p.Ala643Pro)
NC_000019.10:g.11120173G>C
CM000681.2:g.11120173G>C
NC_000019.9:g.11230849G>C
CM000681.1:g.11230849G>C
NC_000019.8:g.11091849G>C
NG_009060.1:g.35793G>C
ENST00000252444.10:c.2185G>C
ENST00000559340.2:c.1787G>C
ENST00000560467.2:c.1807G>C
ENST00000558518.6:c.1927G>C
ENST00000252444.9:c.2181G>C
ENST00000455727.6:c.1423G>C
ENST00000535915.5:c.1804G>C
ENST00000545707.5:c.1546G>C
ENST00000557933.5:c.1927G>C
ENST00000558013.5:c.1927G>C
ENST00000558518.5:c.1927G>C
ENST00000559340.1:c.508G>C
NM_000527.4:c.1927G>C
NM_001195798.1:c.1927G>C
NM_001195799.1:c.1804G>C
NM_001195800.1:c.1423G>C
NM_001195803.1:c.1546G>C
NM_001195798.2:c.1927G>C
NM_001195799.2:c.1804G>C
NM_001195800.2:c.1423G>C
NM_001195803.2:c.1546G>C
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Uncertain Significance

Met criteria codes 2
PP4 PM2
Not Met criteria codes 2
PP3 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.1927G>C (p.Ala643Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for FH (PMID 17539906) after alternative causes of high cholesterol were excluded.
Met criteria codes
PP4
Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible or definite FH criteria (PMID: 17539906) after alternative causes of high cholesterol were excluded.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
PP3
REVEL = 0.686 Does not meet BP4 or PP3 criteria, splicing evaluation required A). Not on limits B). Does not create AG or GT C). There is a GT nearby MES Scores: >var cryptic CTTGTTGCC MAXENT: -25.74 >WT cryptic CTTGTTGGC MAXENT: -14.01 variant cryptic/wild-type cryptic score = -25.74/-14.01 = 1.84 --> it is above 1.1. However, PP3 is not met. When both splice sites have negative MES score, the resulting ratio (-25.74/-14.01=1.84) suggests that there is an increase in relative strengths between these two cryptic splice sites. However, this is misleading as donor with MES of -25.74 is weaker than -14.01 because the former has a smaller number value. Additionally, negative MES score generally suggests a splice site that is unlikely to be used as a bona fide splice site (though there might be some exceptions).
PM5
The NM_000527.5(LDLR):c.1928C>T (p.Ala643Val) is classified as VUS by the FH VCEP guidelines.
Curation History
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