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.1085A>C (p.Asp362Ala)

CA023415

36452 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 40987225-c315-4693-9ec1-385b38754699

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1085A>C

NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala)

NC_000019.10:g.11111538A>C

CM000681.2:g.11111538A>C

NC_000019.9:g.11222214A>C

CM000681.1:g.11222214A>C

NC_000019.8:g.11083214A>C

NG_009060.1:g.27158A>C

ENST00000558518.6:c.1085A>C

ENST00000252444.9:n.1339A>C

ENST00000455727.6:c.581A>C

ENST00000535915.5:c.962A>C

ENST00000545707.5:c.704A>C

ENST00000557933.5:c.1085A>C

ENST00000558013.5:c.1085A>C

ENST00000558518.5:c.1085A>C

ENST00000560173.1:n.84A>C

ENST00000560467.1:n.565A>C

NM_000527.4:c.1085A>C

NM_001195798.1:c.1085A>C

NM_001195799.1:c.962A>C

NM_001195800.1:c.581A>C

NM_001195803.1:c.704A>C

NM_001195798.2:c.1085A>C

NM_001195799.2:c.962A>C

NM_001195800.2:c.581A>C

NM_001195803.2:c.704A>C

Uncertain Significance

PP4 PM2 PS4_Moderate

BA1 BS2 PVS1 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS1 PS2 PS3 PP1 PP3 PP2 PM5 PM3 PM1 PM4 PM6

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.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) 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 = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN≥6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria ≥6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

PP4

Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.

PM2

PopMax MAF = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).

PS4_Moderate

Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN≥6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria ≥6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia.

BA1