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]

Variant: NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585258

251606 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 296222b4-2b23-4455-8916-41dc7d49aa17

Approved on: 2023-01-27

Published on: 2023-04-01

HGVS expressions

NM_000527.5:c.1028G>A

NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)

NC_000019.10:g.11110739G>A

CM000681.2:g.11110739G>A

NC_000019.9:g.11221415G>A

CM000681.1:g.11221415G>A

NC_000019.8:g.11082415G>A

NG_009060.1:g.26359G>A

ENST00000558518.6:c.1028G>A

ENST00000252444.9:n.1282G>A

ENST00000455727.6:c.524G>A

ENST00000535915.5:c.905G>A

ENST00000545707.5:c.647G>A

ENST00000557933.5:c.1028G>A

ENST00000558013.5:c.1028G>A

ENST00000558518.5:c.1028G>A

ENST00000560173.1:n.27G>A

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

NM_000527.4:c.1028G>A

NM_001195798.1:c.1028G>A

NM_001195799.1:c.905G>A

NM_001195800.1:c.524G>A

NM_001195803.1:c.647G>A

NM_001195798.2:c.1028G>A

NM_001195799.2:c.905G>A

NM_001195800.2:c.524G>A

NM_001195803.2:c.647G>A

Likely Pathogenic

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

PM2 PM5_Strong PP4 PP3

PS3 PS4

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>A (p.Gly343Asp) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, 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=0.959, it is above 0.75. PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PM5_Strong: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met. PS4 not met: Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France. PS3 not met: Functional data is not available.

PM2

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

PM5_Strong

Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)(ClinVarID 183106) is classified as Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic by these guidelines, therefore PM5_Strong is met.

PP4

Variant meets PM2 and is identified in 1 index case who fulfil DLCN criteria for definite FH after alternative causes of high cholesterol were excluded, reported in ClinVar (SCV000583778.1) from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France.

PP3

REVEL=0.959, it is above 0.75.

PS3

Functional data is not available.

PS4

Variant meets PM2 and is reported in 1 index case and family fulfil FH criteria, reported from U4M - Lille University & CHRU Lille, Universite de Lille - CHRU de Lille, France.

Curation History

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