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]

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Variant: NM_000527.5(LDLR):c.46C>G (p.Leu16Val)

CA404071705

919564 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: f27b6ec6-e679-4473-85a9-2e64fa05f7c7

Approved on: 2022-08-29

Published on: 2022-12-23

HGVS expressions

NM_000527.5:c.46C>G

NM_000527.5(LDLR):c.46C>G (p.Leu16Val)

NC_000019.10:g.11089594C>G

CM000681.2:g.11089594C>G

NC_000019.9:g.11200270C>G

CM000681.1:g.11200270C>G

NC_000019.8:g.11061270C>G

NG_009060.1:g.5214C>G

ENST00000558518.6:c.46C>G

ENST00000455727.6:c.46C>G

ENST00000535915.5:c.46C>G

ENST00000545707.5:c.46C>G

ENST00000557933.5:c.46C>G

ENST00000557958.1:n.132C>G

ENST00000558013.5:c.46C>G

ENST00000558518.5:c.46C>G

ENST00000560502.5:n.132C>G

NM_000527.4:c.46C>G

NM_001195798.1:c.46C>G

NM_001195799.1:c.46C>G

NM_001195800.1:c.46C>G

NM_001195803.1:c.46C>G

NM_001195798.2:c.46C>G

NM_001195799.2:c.46C>G

NM_001195800.2:c.46C>G

NM_001195803.2:c.46C>G

NR_163945.1:n.66G>C

Uncertain Significance

PM2 BP4

PS3 PS1 PP4 PP3 PM4 PM5 BA1 BS3 BS1 BP3 PVS1

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.46C>G (p.Leu16Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2:This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met. BP4: REVEL= 0.145, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) it creates a GT score in MES: de novo donor = -18.93, authentic donor = 11.08 --- de novo score is <0.8. Variant is not predicted to alter splicing, so BP4 is met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met.

BP4

REVEL= 0.145, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) it creates a GT score in MES: de novo donor = -18.93, authentic donor = 11.08 --- de novo score is <0.8. Variant is not predicted to alter splicing, so BP4 is met.

PS3