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.1028G>T (p.Gly343Val)

CA404082758

440618 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 489ea19a-f7c7-446d-ade9-aae9ee6160ed

Approved on: 2023-04-28

Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1028G>T

NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)

NC_000019.10:g.11110739G>T

CM000681.2:g.11110739G>T

NC_000019.9:g.11221415G>T

CM000681.1:g.11221415G>T

NC_000019.8:g.11082415G>T

NG_009060.1:g.26359G>T

ENST00000558518.6:c.1028G>T

ENST00000252444.9:n.1282G>T

ENST00000455727.6:c.524G>T

ENST00000535915.5:c.905G>T

ENST00000545707.5:c.647G>T

ENST00000557933.5:c.1028G>T

ENST00000558013.5:c.1028G>T

ENST00000558518.5:c.1028G>T

ENST00000560173.1:n.27G>T

ENST00000560467.1:n.541-775G>T

NM_000527.4:c.1028G>T

NM_001195798.1:c.1028G>T

NM_001195799.1:c.905G>T

NM_001195800.1:c.524G>T

NM_001195803.1:c.647G>T

NM_001195798.2:c.1028G>T

NM_001195799.2:c.905G>T

NM_001195800.2:c.524G>T

NM_001195803.2:c.647G>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PM5_Strong PP3 PM2

PS3 PS4 PP4

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.1028G>T (p.Gly343Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5_Strong) 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). PP3: REVEL=0.983, it is above 0.75. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PP4, PS4 not met: Variant meets PM2, and is reported in 1 index case, but the FH diagnosis and clinical information for the patient is not clear, reported by Miyake et al, 2009, National Cardiovascular Center Research Institute, Osaka, Japan, PMID18718593. PS3 not met: Functional data is not available.

PM5_Strong

Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met.

PP3

PP3: REVEL=0.983, it is above 0.75.

PM2

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

PS3

Functional data is not available.

PS4

Variant meets PM2, and is reported in 1 index case, but the FH diagnosis and clinical information for the patient is not clear, reported by Miyake et al, 2009, National Cardiovascular Center Research Institute, Osaka, Japan, PMID18718593.

PP4

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