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.48C>A (p.Leu16=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA085712

250983 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 18e5ecf5-6d86-4789-b174-8536432b1d44

Approved on: 2023-11-07

Published on: 2024-10-03

HGVS expressions

NM_000527.5:c.48C>A

NM_000527.5(LDLR):c.48C>A (p.Leu16=)

NC_000019.10:g.11089596C>A

CM000681.2:g.11089596C>A

NC_000019.9:g.11200272C>A

CM000681.1:g.11200272C>A

NC_000019.8:g.11061272C>A

NG_009060.1:g.5216C>A

ENST00000559340.2:c.48C>A

ENST00000560467.2:c.48C>A

ENST00000558518.6:c.48C>A

ENST00000455727.6:c.48C>A

ENST00000535915.5:c.48C>A

ENST00000545707.5:c.48C>A

ENST00000557933.5:c.48C>A

ENST00000557958.1:n.134C>A

ENST00000558013.5:c.48C>A

ENST00000558518.5:c.48C>A

ENST00000560502.5:n.134C>A

NM_000527.4:c.48C>A

NM_001195798.1:c.48C>A

NM_001195799.1:c.48C>A

NM_001195800.1:c.48C>A

NM_001195803.1:c.48C>A

NM_001195798.2:c.48C>A

NM_001195799.2:c.48C>A

NM_001195800.2:c.48C>A

NM_001195803.2:c.48C>A

NR_163945.1:n.64G>T

Likely Benign

BP7 BP4 PP4 PM2

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.48C>A (p.Leu16=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00006 in Latino population in gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from PMID 7635461 (Ekstrom et al., 1995), Sweden. BP4: Variant is synonymous and splicing evaluation is required. Functional data on splicing is not available. MES: A) Not on limits. B) Not on limits. Variant is not predicted to alter splicing. SpliceAI did not predict alternative splicing (Δ score=0). BP7 met: Variant is synonymous and meets BP4. This variant has 2 supporting evidence codes (BP4, BP7) towards Benign, enough to classify as Likely Benign, and only PM2 and PP4 evidence codes towards Pathogenic, not enough for Likely Pathogenic, so we are confident in classifying this variant as Likely Benign.

BP7

Variant is synonymous and meets BP4.

BP4

Variant is synonymous and splicing evaluation is required. Functional data on splicing is not available. MES: A) Not on limits. B) Not on limits. Variant is not predicted to alter splicing. SpliceAI did not predict alternative splicing (Δ score=0).

PP4

Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for possible FH diagnosis (Child “K” in Table 1, 10 or 11 years old, LDLC 6 mmol/l and LDLC in one parent ≥+2SD), after alternative causes of high cholesterol were excluded. Ekstrom et al, 1995, reported this case in PMID 7635461, from University of Lund, Sweden.

PM2

PopMax MAF=0.00006 in Latino population in gnomAD (gnomAD v2.1.1).

Curation History

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