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>T (p.Ala612=)

CA036837

224618 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7ca66b0a-7663-40c0-9d87-1cd640a32c28

HGVS expressions

NM_000527.5:c.1836C>T

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

NC_000019.10:g.11116989C>T

CM000681.2:g.11116989C>T

NC_000019.9:g.11227665C>T

CM000681.1:g.11227665C>T

NC_000019.8:g.11088665C>T

NG_009060.1:g.32609C>T

ENST00000558518.6:c.1836C>T

ENST00000252444.9:n.2090C>T

ENST00000455727.6:c.1332C>T

ENST00000535915.5:c.1713C>T

ENST00000545707.5:c.1455C>T

ENST00000557933.5:c.1836C>T

ENST00000558013.5:c.1836C>T

ENST00000558518.5:c.1836C>T

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

NM_000527.4:c.1836C>T

NM_001195798.1:c.1836C>T

NM_001195799.1:c.1713C>T

NM_001195800.1:c.1332C>T

NM_001195803.1:c.1455C>T

NM_001195798.2:c.1836C>T

NM_001195799.2:c.1713C>T

NM_001195800.2:c.1332C>T

NM_001195803.2:c.1455C>T

Likely Benign

BP7 BP4

BA1 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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1836C>T (p.Ala612=) variant is classified as likely benign for Familial Hypercholesterolemia by applying evidence code 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: 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 = -16.82, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9 Variant is not predicted to alter splicing. BP7 - Variant is synonymous and meets BP4.

BP7

Variant is synonymous and meets BP4.

BP4

No REVEL, splicing evaluation required. - 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 = -16.82, wt cryptic = -12.61, canonical donor = 4.48. Ratio variant cryptic/wt cryptic: -16.82/-12.61 = 1.33 --- it is above 1.1 Ratio variant cryptic/canonical donor: -16.82/4.48 = -3.75 --- it is not above 0.9 Variant is not predicted to alter splicing.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

PopMax FAF = 0.0002341 (0.03%) in European (non -Finnish) exomes (gnomAD v2.1.1). It is between (0.0002 and 0.002)

Approved on: 2023-04-28

Published on: 2023-05-01

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.