Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1927G>C (p.Ala643Pro)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA10585682

252114 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

Uncertain Significance

PP4 PM2

PP3 PM5

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

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.

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).

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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