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.941-4G>A

CA030790

224619 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 43f1ef31-d52c-44ad-8fe0-b7b8f4dcec03

Approved on: 2023-03-20

Published on: 2023-03-31

HGVS expressions

NM_000527.5:c.941-4G>A

NM_000527.5(LDLR):c.941-4G>A

NC_000019.10:g.11110648G>A

CM000681.2:g.11110648G>A

NC_000019.9:g.11221324G>A

CM000681.1:g.11221324G>A

NC_000019.8:g.11082324G>A

NG_009060.1:g.26268G>A

ENST00000558518.6:c.941-4G>A

ENST00000252444.9:n.1195-4G>A

ENST00000455727.6:c.437-4G>A

ENST00000535915.5:c.818-4G>A

ENST00000545707.5:c.560-4G>A

ENST00000557933.5:c.941-4G>A

ENST00000558013.5:c.941-4G>A

ENST00000558518.5:c.941-4G>A

ENST00000560467.1:n.541-866G>A

NM_000527.4:c.941-4G>A

NM_001195798.1:c.941-4G>A

NM_001195799.1:c.818-4G>A

NM_001195800.1:c.437-4G>A

NM_001195803.1:c.560-4G>A

NM_001195798.2:c.941-4G>A

NM_001195799.2:c.818-4G>A

NM_001195800.2:c.437-4G>A

NM_001195803.2:c.560-4G>A

Benign

BA1 BP4 BS2

BP7 BP2 BS4 BS3 BS1 PP1 PP4 PP3 PM6 PVS1 PM2 PM3 PM5 PM1 PM4 PS1 PS2 PS4 PS3

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.941-4G>A variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP4) 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: BA1 - FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1). BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics. BP4 - No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site MES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64. Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0 B) variant is intronic C) variant is intronic Variant is not predicted to alter splicing.

BA1

FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1), so BA1 is Met.

BP4

No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site MES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64. Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not above 1.0 B) variant is intronic C) variant is intronic Variant is not predicted to alter splicing. --- BP4 is Met.

BS2

Case-level data in VCI indicates this variant is identified in heterozygosity in more than 100 non-FH patients from Ambry Genetics, so BS2 is Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Variant does not meet PM2, so BP2 is Not Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1), so BS1 is not met.

PP1

Segregation data not reported, so PP1 is Not Met.

PP4

Variant does not meet PM2, so PP4 is Not Met.

PP3

No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located at -20 to +3 bases from canonical acceptor splice site MES scores: canonical site variant = 7.03; canonical acceptor wt = 7.64. Ratio variant/wt canonical acceptor: 7.03/7.64 = 0.92 ---- It is not below 0.8 B) variant is intronic C) variant is intronic --- PP3 is not met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

PVS1

Variant is not in canonical +/- 1,2 GT/AG splice site that predict a frameshift, so PVS1 is Not Met.

PM2

PopMax MAF = 0.02610 (2.610%) in African/African American exomes/genomes (gnomAD v2.1.1), so PM2 is not met.

PM3

Variant does not meet PM2, so PM3 is Not Met.

PM5

Variant is in a non-coding region, so PM5 is Not Met.

PM1

Variant does not meet PM2. Also is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.

PM4

Variant does not meet PM2, so PM4 is Not Met.

PS1

Variant is in a non-coding region, so PS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS4

Variant does not meet PM2, so PS4 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

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