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]

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Variant: NM_000527.5(LDLR):c.858C>A (p.Ser286Arg)

CA029904

251488 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7d35f7d3-b40a-4137-ace3-7d0c87f989f6

HGVS expressions

NM_000527.5:c.858C>A

NM_000527.5(LDLR):c.858C>A (p.Ser286Arg)

NC_000019.10:g.11107432C>A

CM000681.2:g.11107432C>A

NC_000019.9:g.11218108C>A

CM000681.1:g.11218108C>A

NC_000019.8:g.11079108C>A

NG_009060.1:g.23052C>A

ENST00000558518.6:c.858C>A

ENST00000252444.9:n.1112C>A

ENST00000455727.6:c.354C>A

ENST00000535915.5:c.735C>A

ENST00000545707.5:c.477C>A

ENST00000557933.5:c.858C>A

ENST00000558013.5:c.858C>A

ENST00000558518.5:c.858C>A

ENST00000558528.1:n.373C>A

ENST00000560467.1:n.458C>A

NM_000527.4:c.858C>A

NM_001195798.1:c.858C>A

NM_001195799.1:c.735C>A

NM_001195800.1:c.354C>A

NM_001195803.1:c.477C>A

NM_001195798.2:c.858C>A

NM_001195799.2:c.735C>A

NM_001195800.2:c.354C>A

NM_001195803.2:c.477C>A

Likely Pathogenic

PS4_Supporting PP4 PP1 PP3 PM2

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

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, PP3 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: PM2 - PopMax MAF = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute). PP3 - REVEL = 0.766. PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation).

PS4_Supporting

Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation).

PP4

Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation).

PP1

Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute)

PP3

REVEL = 0.766.

PM2

PopMax MAF = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).

PS2