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.826T>C (p.Cys276Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585154

251479 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: cd4e74cd-7511-489e-8c09-823f567a973d

Approved on: 2022-10-28

Published on: 2024-12-09

HGVS expressions

NM_000527.5:c.826T>C

NM_000527.5(LDLR):c.826T>C (p.Cys276Arg)

NC_000019.10:g.11107400T>C

CM000681.2:g.11107400T>C

NC_000019.9:g.11218076T>C

CM000681.1:g.11218076T>C

NC_000019.8:g.11079076T>C

NG_009060.1:g.23020T>C

ENST00000252444.10:c.1084T>C

ENST00000559340.2:c.826T>C

ENST00000560467.2:c.826T>C

ENST00000558518.6:c.826T>C

ENST00000252444.9:c.1080T>C

ENST00000455727.6:c.322T>C

ENST00000535915.5:c.703T>C

ENST00000545707.5:c.445T>C

ENST00000557933.5:c.826T>C

ENST00000558013.5:c.826T>C

ENST00000558518.5:c.826T>C

ENST00000558528.1:n.341T>C

ENST00000560467.1:c.426T>C

NM_000527.4:c.826T>C

NM_001195798.1:c.826T>C

NM_001195799.1:c.703T>C

NM_001195800.1:c.322T>C

NM_001195803.1:c.445T>C

NM_001195798.2:c.826T>C

NM_001195799.2:c.703T>C

NM_001195800.2:c.322T>C

NM_001195803.2:c.445T>C

Likely Pathogenic

PS4_Supporting PP4 PP3 PM2 PM1

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

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.826T>C (p.Cys276Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, 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 2022. The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys276. PM2: This variant is absent from gnomAD v2.1.1. PP3: REVEL = 0.915. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH (3 cases from PMID 10978268 (Bertolini et al. 2000)).

PS4_Supporting

Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfill SB criteria for FH from PMID 23375686 and 10978268.

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible criteria for FH from PMID 23375686, after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.915

PM2

This variant is absent from gnomAD v2.1.1

PM1

Variant meets PM2 and is missense in exon 4/alters Cys276.

BP5

Not applicable

BP7

Not a synonymous variant.

BP2

Not met.

BP3

Not applicable

BP4

REVEL = 0.915

BP1

Not applicable

PS2

Not met.

PS3

No functional data.

PS1

Not met.

PP1

Not met.

PP2

Not applicable

BA1

Not met.

PM6

Not met.

PM3

Not met.

PM4

Not an in-frame deletion or insertion.

PM5

Not met.

PVS1

Not a null variant.

BS2

Not identified in normolipidemic individuals

BS4

Not met.

BS3

No functional data.

BS1

Not met.

Curation History

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