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.1204TTC[1] (p.Phe403del)

CA10585356

251731 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 5f27e072-31eb-415e-a56b-be4715f15dab

Approved on: 2023-01-27

Published on: 2024-10-07

HGVS expressions

NM_000527.5(LDLR):c.1204TTC[1] (p.Phe403del)

NM_000527.5:c.1204TTC[1]

NC_000019.10:g.11113298_11113300del

CM000681.2:g.11113298_11113300del

NC_000019.9:g.11223974_11223976del

CM000681.1:g.11223974_11223976del

NC_000019.8:g.11084974_11084976del

NG_009060.1:g.28918_28920del

ENST00000252444.10:c.1465_1467del

ENST00000559340.2:c.1207_1209del

ENST00000560467.2:c.1087_1089del

ENST00000558518.6:c.1207_1209del

ENST00000252444.9:c.1461_1463del

ENST00000455727.6:c.703_705del

ENST00000535915.5:c.1084_1086del

ENST00000545707.5:c.826_828del

ENST00000557933.5:c.1207_1209del

ENST00000558013.5:c.1207_1209del

ENST00000558518.5:c.1207_1209del

ENST00000560173.1:n.206_208del

ENST00000560467.1:c.687_689del

NM_000527.4:c.1207_1209del

NM_001195798.1:c.1207_1209del

NM_001195799.1:c.1084_1086del

NM_001195800.1:c.703_705del

NM_001195803.1:c.826_828del

NM_000527.5:c.1207_1209del

NM_001195798.2:c.1207_1209del

NM_001195799.2:c.1084_1086del

NM_001195800.2:c.703_705del

NM_001195803.2:c.826_828del

Likely Pathogenic

PP4 PM4 PM2 PS4_Supporting

PS2 PS1 PS3 BA1 PP1 PP3 PM3 PM1 PM5 PM6 BS4 BS3 BS1 BS2 BP5 BP2

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.1207_1209del (p.Phe403del) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM4, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1). PM4: Variant meets PM2 and is an in-frame deletion. PS4_Supporting, PP4: Variant meets PM2 and was identified in at least 5 unrelated index cases who fulfill criteria for FH (4 patients from PMID 22698793 (Tichý et al., 2012) and 1 patient from PMID 11462246 (Nauck et al., 2001), reported as 1205delTCT).

PP4

PP4 - Variant meets PM2 and was identified in at least 5 patients meeting clinical FH criteria (PMID: 22698793 and PMID 11462246), after alternative causes of high cholesterol were excluded.

PM4

PM4 - Variant meets PM2 and is an in frame deletion.

PM2

PM2 - Variant is absent from gnomAD (v2.1.1).

PS4_Supporting

PS4_Supporting - Variant meets PM2 and was identified in 4 patients (PMID: 22698793) with MEDPED score of FH and and in 1 patient (PMID 11462246) reported as 1205delTCT with TC 10.33 and LDL-C 8.03.

PS2

No de novo cases were identified.

PS1

Not applicable

PS3

There is no functional evidence in ClinVar for this variant

BA1

Variant is absent from gnomAD (v2.1.1).

PP1

PP1 - no information or report of segregation data/cases

PP3

PP3 - No REVEL (not a missense variant). In silico prediction/evaluation (MaxEnsScan) is not recommended for indels.

PM3

Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.

PM1

PM2 is Met, but variant is not a missense in exon 4 or any of the 60 Cys residues listed. Not applicable.

PM5

Not applicable

PM6

No de novo cases were identified.

BS4

No information or report of segregation data/cases

BS3

There is no functional evidence in ClinVar for this variant

BS1

Variant is absent from gnomAD (v2.1.1).

BS2

Variant not identified in normolipidemic individuals

BP5

not applicable

BP2

Curation History

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