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.1836C>A (p.Ala612=)

CA036811

440665 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 762824a3-7972-4a92-978c-d32cdde15828

HGVS expressions

NM_000527.5:c.1836C>A

NM_000527.5(LDLR):c.1836C>A (p.Ala612=)

NC_000019.10:g.11116989C>A

CM000681.2:g.11116989C>A

NC_000019.9:g.11227665C>A

CM000681.1:g.11227665C>A

NC_000019.8:g.11088665C>A

NG_009060.1:g.32609C>A

ENST00000558518.6:c.1836C>A

ENST00000252444.9:n.2090C>A

ENST00000455727.6:c.1332C>A

ENST00000535915.5:c.1713C>A

ENST00000545707.5:c.1455C>A

ENST00000557933.5:c.1836C>A

ENST00000558013.5:c.1836C>A

ENST00000558518.5:c.1836C>A

ENST00000559340.1:n.426+777C>A

NM_000527.4:c.1836C>A

NM_001195798.1:c.1836C>A

NM_001195799.1:c.1713C>A

NM_001195800.1:c.1332C>A

NM_001195803.1:c.1455C>A

NM_001195798.2:c.1836C>A

NM_001195799.2:c.1713C>A

NM_001195800.2:c.1332C>A

NM_001195803.2:c.1455C>A

Uncertain Significance

PM2 BP7 BP4

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

NM_000527.5(LDLR):c.1836C>A (p.Ala612=) variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence code PM2, BP4 and BP7 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 = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD v2.1.1). Frequency is higher in "other" population exomes and genomes but number of allele is below 10000 BP4 - No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4.

PM2

PopMax MAF = 0.00015 (0.015%) in East Asian exomes and genomes (gnomAD version).

BP7

Variant is synonymous and meets BP4.

BP4

No REVEL, splicing evaluation required. Functional data on splicing not available. - Variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. - There is a GT nearby. MES scores: variant cryptic = -16.35, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.35/-12.61 = 1.30 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.35/4.48 = -3.65 --- it is not above 0.9 Variant is not predicted to alter splicing.

Approved on: 2023-03-20

Published on: 2023-03-31

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