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.1961T>C (p.Leu654Pro)

CA404093213

979168 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 0de395d2-5f72-42ba-b390-c1c0b221781c

Approved on: 2024-10-28

Published on: 2025-01-13

HGVS expressions

NM_000527.5(LDLR):c.1961T>C (p.Leu654Pro)

NM_000527.5:c.1961T>C

NC_000019.10:g.11120207T>C

CM000681.2:g.11120207T>C

NC_000019.9:g.11230883T>C

CM000681.1:g.11230883T>C

NC_000019.8:g.11091883T>C

NG_009060.1:g.35827T>C

ENST00000252444.10:c.2219T>C

ENST00000559340.2:c.*30T>C

ENST00000560467.2:c.1841T>C

ENST00000558518.6:c.1961T>C

ENST00000252444.9:c.2215T>C

ENST00000455727.6:c.1457T>C

ENST00000535915.5:c.1838T>C

ENST00000545707.5:c.1580T>C

ENST00000557933.5:c.1961T>C

ENST00000558013.5:c.1961T>C

ENST00000558518.5:c.1961T>C

ENST00000559340.1:c.542T>C

NM_000527.4:c.1961T>C

NM_001195798.1:c.1961T>C

NM_001195799.1:c.1838T>C

NM_001195800.1:c.1457T>C

NM_001195803.1:c.1580T>C

NM_001195798.2:c.1961T>C

NM_001195799.2:c.1838T>C

NM_001195800.2:c.1457T>C

NM_001195803.2:c.1580T>C

Uncertain Significance

PP4 PP3 PM2 PS4_Supporting

BA1 BP7 BP5 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP2 PM6 PM1 PM3 PM5 PM4 PS2 PS1 PS3 PVS1

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.1961T>C (p.Leu654Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, 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). PP3: REVEL = 0.911. PS4_Supporting, PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill modified DLCN criteria >=6 from Setia et al., 2020 (PMID 32044282).

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 PMID: 32044282

PP3

REVEL = 0.911. It is above 0.75, so PP3 is met.

PM2

This variant is absent from gnomAD (gnomAD v4.1).

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases who fulfill modified DLCN criteria>=6 from PMID: 32044282

BA1

This variant is absent from gnomAD (gnomAD v4.1).

BP7

Missense variant

BP5

Not applicable

BP2

Not identified in index cases with more than one variant

BP3

Missense variant

BP4

REVEL not below 0.5, therefore BP4 is not met

BP1

Not applicable

BS4

No non-segregation reported

BS3

not met (no information or reports of functional data).

BS1

This variant is absent from gnomAD (gnomAD v4.1).

BS2

Not identified in normolipidemic controls

PP1

PP1: from PMID:32044282 (Table 2), segregation in 1/2 family members is indicated, and it is stated that "positive segregation was indicated in family members with premature CAD or historical LDL-C elevations". However phenotype of relatives are unclear, and therefore this data was not considered.

PP2

Not applicable

PM6

No de novo occurrence

PM1

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

PM3

Not identified in index cases with more than one variant

PM5

NM_000527.5(LDLR):c.1960C>T (p.Leu654Phe) (ClinVar ID: 252132) considered as VUS by these guidelines.

PM4

Missense variant

PS2

No de novo occurrence

PS1

No variant with same amino acid change identified as pathogenic

PS3

not met (no information or reports of functional data).

PVS1

Missense variant

Curation History

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