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.1024G>A (p.Asp342Asn)

CA023404

161274 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ce995e23-c06d-45fb-9806-e3589bf1dff2

Approved on: 2021-12-13

Published on: 2022-01-01

HGVS expressions

NM_000527.5:c.1024G>A

NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn)

NC_000019.10:g.11110735G>A

CM000681.2:g.11110735G>A

NC_000019.9:g.11221411G>A

CM000681.1:g.11221411G>A

NC_000019.8:g.11082411G>A

NG_009060.1:g.26355G>A

ENST00000558518.6:c.1024G>A

ENST00000252444.9:n.1278G>A

ENST00000455727.6:c.520G>A

ENST00000535915.5:c.901G>A

ENST00000545707.5:c.643G>A

ENST00000557933.5:c.1024G>A

ENST00000558013.5:c.1024G>A

ENST00000558518.5:c.1024G>A

ENST00000560173.1:n.23G>A

ENST00000560467.1:n.541-779G>A

NM_000527.4:c.1024G>A

NM_001195798.1:c.1024G>A

NM_001195799.1:c.901G>A

NM_001195800.1:c.520G>A

NM_001195803.1:c.643G>A

NM_001195798.2:c.1024G>A

NM_001195799.2:c.901G>A

NM_001195800.2:c.520G>A

NM_001195803.2:c.643G>A

Benign

BP4 BA1

PS2 PS4 PS3 PS1 BP2 BP3 BP1 BP5 BP7 PVS1 PP4 PP1 PP3 PP2 PM6 PM2 PM3 PM1 PM4 PM5 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1024G>A (p.Asp342Asn) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1 and BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met. BP4 - REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT. Variant is not predicted to alter splicing, so BP4 is met.

BP4

REVEL = 0.283. it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT Variant is not predicted to alter splicing, so BP4 is met

BA1

FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). It is above 0.5%, so BA1 is met

PS2

no de novo occurrence was identified

PS4

PM2 is not met, so PS4 is not met

PS3

there are no published functional studies for this variant

PS1

no other missense variant leads to the same amino acid change

BP2

variant identified in: - 1 index case with LDLR, c.1118G>A, p.Gly373Asp from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies --- no phenotype specified - 1 index case with LDLR, c.2312C>T, p.Ala771Val from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies --- no phenotype specified - 1 Index case with NM_000527.5(LDLR):c.1201C>G (p.Leu401Val) (no information about cis or trans); LDL-C 281 mg/dL without pharmacological treatment from Laboratory of Genetics and Molecular Cardiology --- no information about cis or trans - 1 index case who is heterozygous for LDLR c.6delG variant (phase unknown); LDL ~200 and TC 276 from Ambry phase unknown so not met

BP3

not applicable

BP1

not applicable

BP5

not applicable

BP7

variant is missense, so not applicable

PVS1

variant is missense and not in initiation codon, not applicable

PP4

PM2 is not met, so PP4 is not met

PP1

no family members were tested

PP3

REVEL = 0.283, it is not above 0.75, splicing evaluation is required. A) not on limits B) variant is exonic and at least 50bp downstream from canonical acceptor site but it does not create GT C) there is no GT nearby so PP3 is not met

PP2

not applicable

PM6

no de novo occurrence was identified

PM2

PopMax MAF = 0.006414 (0.64%) in African exomes (gnomAD v2.1.1). It is not below 0.02%, so not met

PM3

PM2 is not met, so PM3 is not met

PM1

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

PM4

variant is missense, so not applicable

PM5

2 other missense variants in the same codon: NM_000527.5(LDLR):c.1024G>T (p.Asp342Tyr) - VUS by these guidelines NM_000527.5(LDLR):c.1026C>G (p.Asp342Glu) - VUS by these guidelines so not met

BS2

not identified in normolipidemic individuals

BS4

no family members were tested

BS3

there are no published functional studies for this variant

BS1

FAF = 0.005579 (0.56%) in African exomes (gnomAD v2.1.1). BA1 is met, so BS1 is not met

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