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.251C>T (p.Pro84Leu)

CA10576272

226310 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 07c7b461-166a-4594-a32f-e4d763eef195

HGVS expressions

NM_000527.5:c.251C>T

NM_000527.5(LDLR):c.251C>T (p.Pro84Leu)

NC_000019.10:g.11102724C>T

CM000681.2:g.11102724C>T

NC_000019.9:g.11213400C>T

CM000681.1:g.11213400C>T

NC_000019.8:g.11074400C>T

NG_009060.1:g.18344C>T

ENST00000558518.6:c.251C>T

ENST00000252444.9:n.505C>T

ENST00000455727.6:c.251C>T

ENST00000535915.5:c.190+2379C>T

ENST00000545707.5:c.251C>T

ENST00000557933.5:c.251C>T

ENST00000557958.1:n.337C>T

ENST00000558013.5:c.251C>T

ENST00000558518.5:c.251C>T

NM_000527.4:c.251C>T

NM_001195798.1:c.251C>T

NM_001195799.1:c.190+2379C>T

NM_001195800.1:c.251C>T

NM_001195803.1:c.251C>T

NM_001195798.2:c.251C>T

NM_001195799.2:c.190+2379C>T

NM_001195800.2:c.251C>T

NM_001195803.2:c.251C>T

Uncertain Significance

PP4 PM2 PP1_Moderate

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.251C>T (p.Pro84Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code PM2, PP1_Moderate 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) PP1_Moderate - Variant segregates with FH phenotype in at least 4 informative meiosis from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). In one family 2 family members positive for variant with LDL > 75th percentile, in the other 2 family members negative for variantwith LDL < 50th percentile. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) after alternative causes of high cholesterol were excluded.

PP4

Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) after alternative causes of high cholesterol were excluded.

PM2

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

PP1_Moderate

Variant segregates with FH phenotype in at least 4 informative meiosis from 2 families from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA). In one family 2 family members positive for variant with LDL > 75th percentile, in the other 2 family members negative for variantwith LDL < 50th percentile.

BP4

REVEL = 0.666, it is not below 0.50

PP3

REVEL = 0.666, 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 = -7.00, wt cryptic = -6.77, canonical donor = 9.90. Ratio variant cryptic/wt cryptic: -7,00/-6.77 = 1,03 --- it is not above 1.1 Ratio variant cryptic/canonical donor: -7.00/9,90 = -0,71 --- 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.250C>T (p.Pro84Ser) Uncertain significance - insufficient evidence by these guidelines. - NM_000527.5(LDLR):c.251C>G (p.Pro84Arg) Uncertain significance - insufficient evidence by these guidelines. There are 2 variants in the same codon classified as Uncertain significance - insufficient evidence by these guidelines. PS4 is not met Variant meets PM2 but is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA).

Approved on: 2023-03-20

Published on: 2023-03-31

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