Evidence Repository
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.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
More

Benign

Met criteria codes 3
BA1 BS2 BP4
Not Met criteria codes 19
PVS1 PS1 PS2 PS4 PS3 PP1 PP4 PP3 PM6 PM2 PM3 PM5 PM1 PM4 BS4 BS3 BS1 BP7 BP2

Evidence Links 0

Expert Panel

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.
Met criteria codes
BA1
FAF = 0.02478 (2.478%) in African/African American exomes (gnomAD v2.1.1), so BA1 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.
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.
Not Met criteria codes
PVS1
Variant is not in canonical +/- 1,2 GT/AG splice site that predict a frameshift, so PVS1 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.
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.
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.
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.
BP7
Variant is not synonymous, so BP7 is Not Met.
BP2
Variant does not meet PM2, so BP2 is Not Met.
Curation History
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