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.1432G>T (p.Gly478Trp)

CA404085992

548076 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: d4e8f2e5-1bec-4614-8a2f-e85ce94c2aa3

HGVS expressions

NM_000527.5:c.1432G>T

NM_000527.5(LDLR):c.1432G>T (p.Gly478Trp)

NC_000019.10:g.11113608G>T

CM000681.2:g.11113608G>T

NC_000019.9:g.11224284G>T

CM000681.1:g.11224284G>T

NC_000019.8:g.11085284G>T

NG_009060.1:g.29228G>T

ENST00000558518.6:c.1432G>T

ENST00000252444.9:n.1686G>T

ENST00000455727.6:c.928G>T

ENST00000535915.5:c.1309G>T

ENST00000545707.5:c.1051G>T

ENST00000557933.5:c.1432G>T

ENST00000558013.5:c.1432G>T

ENST00000558518.5:c.1432G>T

ENST00000559340.1:n.153G>T

ENST00000560467.1:n.912G>T

NM_000527.4:c.1432G>T

NM_001195798.1:c.1432G>T

NM_001195799.1:c.1309G>T

NM_001195800.1:c.928G>T

NM_001195803.1:c.1051G>T

NM_001195798.2:c.1432G>T

NM_001195799.2:c.1309G>T

NM_001195800.2:c.928G>T

NM_001195803.2:c.1051G>T

Uncertain Significance

PP3 PM5 PM2

BA1 PP4 PP1 PP2 PM3 PM1 PM4 PM6 PVS1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1

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.1432G>T (p.Gly478Trp) 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 - 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4) - Pathogenic by these guidelines (FH VCEP training Aug 2021) (2) NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) - 0 stars, Pathogenic - Likely pathogenic by these guidelines --- 1 Pathogenic variant in the same codon, so PM5 is met. PP3 - REVEL = 0.985. It is above 0.75, so PP3 is met.

PP3

REVEL = 0.985. It is above 0.75, so PP3 is met

PM5

2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) - 1 star, Conflicting interpretations of pathogenicity: Likely pathogenic(8);Pathogenic(1);Uncertain significance(4) in ClinVar - Pathogenic by these guidelines (FH VCEP training Aug 2021) (2) NM_000527.4(LDLR):c.1433G>A (p.Gly478Glu) - 0 stars, Pathogenic in ClinVar - Likely pathogenic by these guidelines 1 Pathogenic variant in the same codon, so PM5 is met

PM2

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

BA1

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

PP4

there is no case data for this variant, so not met

PP1

there is no case data for this variant, so not met

PP2

not applicable

PM3

there is no case data for this variant, so not met

PM1

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

PM4

variant is missense, so not applicable

PM6

there is no case data for this variant, so not met

PVS1

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

BS4

there is no case data for this variant, so not met

BS3

there are no published functional studies for this variant

BS1

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

BS2

there is no case data for this variant, so not met

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

there is no case data for this variant, so not met

BP3

not applicable

BP4

REVEL = 0.985. It is not below 0.50, so BP4 is not met

BP1

not applicable

PS2

there is no case data for this variant, so not met

PS4

there is no case data for this variant, so not met

PS3

there are no published functional studies for this variant

PS1

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

Approved on: 2022-01-28

Published on: 2022-07-11

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.