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.1960C>T (p.Leu654Phe)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585697

252132 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5df6685f-9e7e-4f39-b88c-466495217619

Approved on: 2024-10-28

Published on: 2025-01-13

HGVS expressions

NM_000527.5:c.1960C>T

NM_000527.5(LDLR):c.1960C>T (p.Leu654Phe)

NC_000019.10:g.11120206C>T

CM000681.2:g.11120206C>T

NC_000019.9:g.11230882C>T

CM000681.1:g.11230882C>T

NC_000019.8:g.11091882C>T

NG_009060.1:g.35826C>T

ENST00000252444.10:c.2218C>T

ENST00000559340.2:c.*29C>T

ENST00000560467.2:c.1840C>T

ENST00000558518.6:c.1960C>T

ENST00000252444.9:c.2214C>T

ENST00000455727.6:c.1456C>T

ENST00000535915.5:c.1837C>T

ENST00000545707.5:c.1579C>T

ENST00000557933.5:c.1960C>T

ENST00000558013.5:c.1960C>T

ENST00000558518.5:c.1960C>T

ENST00000559340.1:c.541C>T

NM_000527.4:c.1960C>T

NM_001195798.1:c.1960C>T

NM_001195799.1:c.1837C>T

NM_001195800.1:c.1456C>T

NM_001195803.1:c.1579C>T

NM_001195798.2:c.1960C>T

NM_001195799.2:c.1837C>T

NM_001195800.2:c.1456C>T

NM_001195803.2:c.1579C>T

Uncertain Significance

PP1 PP4 PM2 PS4_Supporting

PS1 PS2 PS3 PP3 PP2 PM6 PM5 PM1 PM3 PM4 PVS1 BA1 BS2 BS3 BS4 BS1 BP7 BP5 BP2 BP3 BP4 BP1

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.1960C>T (p.Leu654Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 index cases fulfilling Simon Broome criteria for possible FH criteria, after alternative causes of high cholesterol were excluded, from the Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal. PP1: Variant segregates with FH phenotype in at least 2 informative meioses from 1 family (Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal): 1 affected family member has the variant and 1 unaffected family member does not have the variant.

PP1

Variant segregates with FH phenotype in 2 informative meioses identified by Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge - data from 1 family (1 family member positive for variant with LDL-C >75th percentil and 1 family member negative for variant with LDL-C <50th percentil)

PP4

Variant meets PM2 and is identified in at least 1 index case fulfilling Simon Broome criteria for possible FH criteria, after alternative causes of high cholesterol were excluded, from the Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1 and v4.1).

PS4_Supporting

Variant meets PM2 and is identified in at least 3 index cases fulfilling Simon Broome criteria for possible FH criteria, after alternative causes of high cholesterol were excluded, from the Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

PS1

No variant with same amino acid change identified as pathogenic

PS2

No de novo occurrence

PS3

Functional studies (PMID: 37719435) performed using heterologous cells (CHO), microscopy assays - results - 79-84% LDLR expression and 89-100% LDLR activity. ----- Overall, the results are not below 70% and not above 90%, so PS3 and BS3 are not met either.

PP3

REVEL = 0.72. It is not above 0.75, splicing evaluation needed. Functional data on slipicing not available. A) not on limits; B) does not create GT or AG; C) variant fits into "de novo donor" limits and there is a GT nearby. Therefore, splicing needs evaluation: wt cryptic (TTCTCTTCC) = -42.45, variant cryptic (TTTTCTTCC)= -43.46, cannonical donnor (GAGGTAAGG) = 10.28. The scores are negative, so the variant is not predicted to affect splicing. Therefore, PP3 is not met.

PP2

Not applicable

PM6

No de novo occurrence

PM5

NM_000527.5(LDLR):c.1961T>C (p.Leu654Pro) (ClinVar ID: 979168) considered as VUS by these guidelines.

PM1

Variant meets PM2 but is not located in exon 4 and is not one of the 60 highly conserved cysteine residues

PM3

Not identified in index cases with more than one variant

PM4

Missense variant

PVS1

Missense variant

BA1

This variant is absent from gnomAD (gnomAD v2.1.1 and v4.1).

BS2

Not identified in normolipidemic controls

BS3

BS4

No non-segregation identified

BS1

This variant is absent from gnomAD (gnomAD v2.1.1 and v4.1).

BP7

Missense variant

BP5

Not applicable

BP2

Not identified in index cases with more than one variant

BP3

BP4

REVEL = 0.72, not bellow 0.50. Therefore, BP4 is not met.

BP1

Not applicable

Curation History

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