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.2479G>T (p.Val827Phe)

CA16602353

375840 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ad250858-bb45-464e-a96e-b94160859000

Approved on: 2022-01-28

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.2479G>T

NM_000527.5(LDLR):c.2479G>T (p.Val827Phe)

NC_000019.10:g.11129602G>T

CM000681.2:g.11129602G>T

NC_000019.9:g.11240278G>T

CM000681.1:g.11240278G>T

NC_000019.8:g.11101278G>T

NG_009060.1:g.45222G>T

ENST00000558518.6:c.2479G>T

ENST00000252444.9:n.2733G>T

ENST00000455727.6:c.1975G>T

ENST00000535915.5:c.2356G>T

ENST00000545707.5:c.1945G>T

ENST00000557933.5:c.2541G>T

ENST00000558013.5:c.2479G>T

ENST00000558518.5:c.2479G>T

ENST00000560628.1:n.108+1948G>T

NM_000527.4:c.2479G>T

NM_001195798.1:c.2479G>T

NM_001195799.1:c.2356G>T

NM_001195800.1:c.1975G>T

NM_001195803.1:c.1945G>T

NM_001195798.2:c.2479G>T

NM_001195799.2:c.2356G>T

NM_001195800.2:c.1975G>T

NM_001195803.2:c.1945G>T

Uncertain Significance

PP3 PM2

PS2 PS4 PS3 PS1 PP4 PP1 PP2 PM3 PM1 PM4 PM5 PM6 BA1 BS2 PVS1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

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.2479G>T (p.Val827Phe) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 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. PP3 - REVEL = 0.86. It is above 0.75, so PP3 is met

PP3

REVEL = 0.86. It is above 0.75, so PP3 is met

PM2

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

PS2

there is no case data

PS4

there is no case data

PS3

there are no published functional studies for this variant

PS1

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

PP4

there is no case data

PP1

there is no case data

PP2

not applicable

PM3

there is no case data

PM1

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

PM4

variant is missense, so not met

PM5

2 more missense variants in same codon: (1) NM_000527.5(LDLR):c.2479G>A (p.Val827Ile) - 3 stars, VUS by these guidelines (FH VCEP) in ClinVar (2) NM_000527.5(LDLR):c.2480T>A (p.Val827Asp) - 1 star, VUS in ClinVar - VUS by these guidelines no Pathogenic by these guidelines, so not met

PM6

there is no case data

BA1

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

BS2

there is no case data

PVS1

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

BS4

there is no case data

BS3

there are no published functional studies for this variant

BS1

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

BP5

not applicable

BP7

variant is missense, so not met

BP2

there is no case data

BP3

not applicable

BP4

REVEL = 0.86. It is not below 0.50, so BP4 is not met

BP1

not applicable

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