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.259T>C (p.Trp87Arg)

CA404075655

440552 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9698a1b6-b4f5-4900-938d-4a063ce16f60

HGVS expressions

NM_000527.5:c.259T>C

NM_000527.5(LDLR):c.259T>C (p.Trp87Arg)

NC_000019.10:g.11102732T>C

CM000681.2:g.11102732T>C

NC_000019.9:g.11213408T>C

CM000681.1:g.11213408T>C

NC_000019.8:g.11074408T>C

NG_009060.1:g.18352T>C

ENST00000558518.6:c.259T>C

ENST00000252444.9:n.513T>C

ENST00000455727.6:c.259T>C

ENST00000535915.5:c.190+2387T>C

ENST00000545707.5:c.259T>C

ENST00000557933.5:c.259T>C

ENST00000557958.1:n.345T>C

ENST00000558013.5:c.259T>C

ENST00000558518.5:c.259T>C

NM_000527.4:c.259T>C

NM_001195798.1:c.259T>C

NM_001195799.1:c.190+2387T>C

NM_001195800.1:c.259T>C

NM_001195803.1:c.259T>C

NM_001195798.2:c.259T>C

NM_001195799.2:c.190+2387T>C

NM_001195800.2:c.259T>C

NM_001195803.2:c.259T>C

Uncertain Significance

PM5 PM2 PP3

PS2 PS3 PS1 PM4 PM3 PM1 PM6 BA1 PVS1 BP7 BP5 BP3 BP2 BP4 BP1 BS4 BS3 BS1 BS2 PP4 PP1 PP2

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.259T>C (p.Trp87Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM5 and PP3) 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), so PM2 is met. PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) - Pathogenic by expert panel in ClinVar, so PM5 is met. PP3 - REVEL = 0.891. It is above 0.75, so PP3 is met.

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) - Pathogenic by expert panel in ClinVar so PM5 is met

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met

PP3

REVEL = 0.891. It is above 0.75, so PP3 is met

PS2

there is no report of this variant appearing de novo

PS3

This variant was not studied in a functional study

PS1

no other variant leads to the same amino acid change, so not met

PM4

variant is missense, so not applicable

PM3

there were no other variants identified in index cases

PM1

variant is missense and meets PM2, but it is not in exon 4 and not does not alter Cys, so not met

PM6

there is no report of this variant appearing de novo

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), so not met

PVS1

variant is missense and not in initiation codon, so not applicable

BP7

variant is missense, so not applicable

BP5

not applicable

BP3

not applicable

BP2

there were no other variants identified in index cases

BP4

REVEL = 0.891. It is not below 0.50, so not met

BP1

not applicable

BS4

there is no segregation data for this variant

BS3

This variant was not studied in a functional study

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), so not met

BS2

variant was not searched in normolipidemic individuals

PP4

variant meets PM2 and was identified in: - 1 index case from Mayo lab with clinical DLCN 1. so not met

PP1

there is no segregation data for this variant

PP2

not applicable

Approved on: 2021-12-13

Published on: 2022-07-11

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