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.1988-5C>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA038064

252152 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 645c326e-0d97-4d1d-bd1a-a57fde168448

Approved on: 2025-01-31

Published on: 2025-03-24

HGVS expressions

NM_000527.5:c.1988-5C>G

NM_000527.5(LDLR):c.1988-5C>G

NC_000019.10:g.11120365C>G

CM000681.2:g.11120365C>G

NC_000019.9:g.11231041C>G

CM000681.1:g.11231041C>G

NC_000019.8:g.11092041C>G

NG_009060.1:g.35985C>G

ENST00000252444.10:c.2246-5C>G

ENST00000559340.2:c.*57-5C>G

ENST00000560467.2:c.1868-5C>G

ENST00000558518.6:c.1988-5C>G

ENST00000252444.9:c.2242-5C>G

ENST00000455727.6:c.1484-5C>G

ENST00000535915.5:c.1865-5C>G

ENST00000545707.5:c.1606+132C>G

ENST00000557933.5:c.1988-5C>G

ENST00000558013.5:c.1988-5C>G

ENST00000558518.5:c.1988-5C>G

ENST00000559340.1:c.569-5C>G

NM_000527.4:c.1988-5C>G

NM_001195798.1:c.1988-5C>G

NM_001195799.1:c.1865-5C>G

NM_001195800.1:c.1484-5C>G

NM_001195803.1:c.1606+132C>G

NM_001195798.2:c.1988-5C>G

NM_001195799.2:c.1865-5C>G

NM_001195800.2:c.1484-5C>G

NM_001195803.2:c.1606+132C>G

Uncertain Significance

PP3

PS4 PP4 PM2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1988-5C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PP3: No REVEL. Splicing evaluation required. Functional data on splicing not available. Variant is located at -20 to +3 bases from canonical acceptor splice site. MES scores: variant score = 7.59; wt score = 15.87. Ratio var score/wt score = 0.478. It is below 0.8 so PP3 is met.

PP3

PP3 - No REVEL. Splicing evaluation required. Functional data on splicing not available. Variant is located at -20 to +3 bases from canonical acceptor splice site. MES scores: variant score = 7.59; wt score = 15.87. Ratio var score/wt score = 0.478. It is below 0.8 so PP3 is met.

PS4

PS4 - Variant is identified in 1 patient from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN score >=6. and 1 patient with with possible FH based on Simon Broome FH score (PMID: 20236128) but PM2 is not Met. So, PS4 is not Met

PP4

PP4_supporting- Variant is identified in 1 patient from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN score >=6. and 1 patient with with possible FH based on Simon Broome FH score (PMID: 20236128) after alternative causes of high cholesterol were excluded, but PM2 is not Met. So, PP4 is not Met.

PM2

PopMax MAF=0.002060 (0.2%) in Ashkenazi Jewish exomes+genomes (gnomAD v4.1.0). So, PM2 is not Met

Curation History

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