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.250C>T (p.Pro84Ser)

CA10584809

251094 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c79042aa-3408-4532-83a1-6730dde53e95

HGVS expressions

NM_000527.5:c.250C>T

NM_000527.5(LDLR):c.250C>T (p.Pro84Ser)

NC_000019.10:g.11102723C>T

CM000681.2:g.11102723C>T

NC_000019.9:g.11213399C>T

CM000681.1:g.11213399C>T

NC_000019.8:g.11074399C>T

NG_009060.1:g.18343C>T

ENST00000558518.6:c.250C>T

ENST00000252444.9:n.504C>T

ENST00000455727.6:c.250C>T

ENST00000535915.5:c.190+2378C>T

ENST00000545707.5:c.250C>T

ENST00000557933.5:c.250C>T

ENST00000557958.1:n.336C>T

ENST00000558013.5:c.250C>T

ENST00000558518.5:c.250C>T

NM_000527.4:c.250C>T

NM_001195798.1:c.250C>T

NM_001195799.1:c.190+2378C>T

NM_001195800.1:c.250C>T

NM_001195803.1:c.250C>T

NM_001195798.2:c.250C>T

NM_001195799.2:c.190+2378C>T

NM_001195800.2:c.250C>T

NM_001195803.2:c.250C>T

Uncertain Significance

PP4 PM2

BP4 PP3 PM5

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.250C>T (p.Pro84Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from PMID 11810272

PP4

PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from PMID 11810272

PM2

This variant is absent from gnomAD (gnomAD v2.1.1)

BP4

REVEL = 0.622, it is not below 0.50

PP3

REVEL = 0.622, it is not above 0.75, 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 = -38.14, wt cryptic = -37.91, canonical donor = 9.90. Ratio variant cryptic/wt cryptic: -38.14/-37,91 = 1,01 --- it is not above 1.1 Ratio variant cryptic/canonical donor: -38,14/9,90 = -3,85 --- it is not above 0.9 - Variant is exonic and at least 50bp upstream from canonical donor site but it does not create AG. there is no AG nearby

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.251C>G (p.Pro84Arg) Uncertain significance - insufficient evidence by these guidelines. - NM_000527.5(LDLR):c.251C>T (p.Pro84Leu) Uncertain significance - insufficient evidence by these guidelines. There are 2 variants in the same codon classified as Uncertain significance - insufficient evidence by these guidelines.

Approved on: 2023-03-20

Published on: 2023-03-31

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.