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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del)

CA10585351

251727 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 77439a5e-7345-4771-8826-a2b0da5d2645

HGVS expressions

NM_000527.5:c.1199_1207del

NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del)

NC_000019.10:g.11113290_11113298del

CM000681.2:g.11113290_11113298del

NC_000019.9:g.11223966_11223974del

CM000681.1:g.11223966_11223974del

NC_000019.8:g.11084966_11084974del

NG_009060.1:g.28910_28918del

ENST00000558518.6:c.1199_1207del

ENST00000252444.9:n.1453_1461del

ENST00000455727.6:c.695_703del

ENST00000535915.5:c.1076_1084del

ENST00000545707.5:c.818_826del

ENST00000557933.5:c.1199_1207del

ENST00000558013.5:c.1199_1207del

ENST00000558518.5:c.1199_1207del

ENST00000560173.1:n.198_206del

ENST00000560467.1:n.679_687del

NM_000527.4:c.1199_1207del

NM_001195798.1:c.1199_1207del

NM_001195799.1:c.1076_1084del

NM_001195800.1:c.695_703del

NM_001195803.1:c.818_826del

NM_001195798.2:c.1199_1207del

NM_001195799.2:c.1076_1084del

NM_001195800.2:c.695_703del

NM_001195803.2:c.818_826del

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PS4 PM2 PM4 PP4

PS2 PS3 PS1 PM6 PM3 PM1 PM5 BA1 PVS1 BP2 BP3 BP4 BS4 BS3 BS1 BS2 PP1 PP3

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1199_1207del (p.Tyr400_Phe402del) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM4, and PP4 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: PS4: Variant meets PM2 and is identified in 19 unrelated FH index cases (18 with DLCN criteria>=6 from PMID: 18243212 (Alonso et al., 2008), and 1 with DLCN criteria from PMID 27784735 (Sánchez-Hernández et al.,2016)). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM4: Variant meets PM2 and is in frame deletion. So PM4 is met. PP4: Variant meets PM2 and is identified in 19 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.

PS4

Variant meets PM2 and is identified in 19 unrelated FH index cases (18 with DLCN criteria>=6 from PMID: 18243212 (Alonso et al., 2008), and 1 with DLCN criteria from PMID 27784735 (Sánchez-Hernández et al.,2016)). So PS4 is met.

PM2

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

PM4

Variant meets PM2 and is in frame deletion. So PM4 is met.

PP4

Variant meets PM2 and is identified in 19 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

No data available

PS1

It is not a missense variant.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

No data available.

PM1

Not a missense variant

PM5

It is not a missense variant.

BA1

This variant is absent from gnomAD (gnomAD v2.1.1).

PVS1

Not nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion

BP2

No data available.

BP3

in-frame deletion in a non-repeat region

BP4

It is not a missense variant.

BS4

No data available.

BS3

No data available

BS1

This variant is absent from gnomAD (gnomAD v2.1.1).

BS2

No data available

PP1

No data available.

PP3

It is not a missense variant.

Approved on: 2023-03-20

Published on: 2023-03-31

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