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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.2140+1G>A

CA023643

3744 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 3baa34ee-ff35-4201-b317-1815827dce8e

HGVS expressions

NM_000527.5:c.2140+1G>A
NM_000527.5(LDLR):c.2140+1G>A
NC_000019.10:g.11120523G>A
CM000681.2:g.11120523G>A
NC_000019.9:g.11231199G>A
CM000681.1:g.11231199G>A
NC_000019.8:g.11092199G>A
NG_009060.1:g.36143G>A
ENST00000558518.6:c.2140+1G>A
ENST00000252444.9:n.2394+1G>A
ENST00000455727.6:c.1636+1G>A
ENST00000535915.5:c.2017+1G>A
ENST00000545707.5:c.1606+290G>A
ENST00000557933.5:c.2140+1G>A
ENST00000558013.5:c.2140+1G>A
ENST00000558518.5:c.2140+1G>A
NM_000527.4:c.2140+1G>A
NM_001195798.1:c.2140+1G>A
NM_001195799.1:c.2017+1G>A
NM_001195800.1:c.1636+1G>A
NM_001195803.1:c.1606+290G>A
NM_001195798.2:c.2140+1G>A
NM_001195799.2:c.2017+1G>A
NM_001195800.2:c.1636+1G>A
NM_001195803.2:c.1606+290G>A

Pathogenic

Met criteria codes 6
PM2 PP1_Strong PVS1 PS3_Supporting PS4_Moderate PP4
Not Met criteria codes 20
PS2 PS1 PM6 PM3 PM1 PM4 PM5 BA1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.2140+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PP1_Strong, PM2, PS4_Moderate, PP4 and PS3_Supporting) 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: PVS1 - Variant is in canonical splice site and predicts a frameshift in exon 15. PP1_strong - Variant segregates with FH phenotype in 9 members of 4 families (9 informative meioses). PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 7 unrelated index cases fulfilling validated clinical criteria for FH from different labs. PP4 - Variant meets PM2. Variant found in 7 unrelated index cases fulfilling validated clinical criteria for FH. PS3_supporting - PMID:12522687 - Level 3 assay - study on htz patient's lymphocytes. An additional mRNA transcript of ~730 bp was detected; 214 bp retention of intron 14 causing a premature stop codon 99 amino acids later was the identified using cDNA sequencing. 46% LDLR particle clearance.
Met criteria codes
PM2
No population data was found for this allele in gnomAD (gnomAD v2.1.1).
PP1_Strong
Variant segregates with FH phenotype in 9 members of 4 families (9 informative meioses).
PVS1
Variant is in canonical splice site and predicts a frameshift in exon 15.
PS3_Supporting
PMID:12522687 - Level 3 assay - study on htz patient's lymphocytes. An additional mRNA transcript of ~730 bp was detected; 214 bp retention of intron 14 causing a premature stop codon 99 amino acids later was the identified using cDNA sequencing. 46% LDLR particle clearance.
PS4_Moderate
Variant meets PM2. Variant identified in 7 unrelated index cases (1 case from Color laboratory with Simon-Broome criteria; 2 cases from Ambry Genetics with Simon-Broome criteria; 1 case from GeneDx Inc. with Simon-Broome criteria; 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon_Broome criteria, 1 case from University of British Columbia with DLCN criteria ).
PP4
Variant meets PM2. Variant found in 7 unrelated index cases fulfilling validated clinical criteria for FH (see PS4_Moderate).
Not Met criteria codes
PS2
No de novo cases were identified.
PS1
Intronic variant. Not applicable.
PM6
No de novo cases were identified.
PM3
Not identified in individuals with other variants.
PM1
Intronic variant. Not applicable.
PM4
Intronic variant. Not applicable.
PM5
Intronic variant. Not applicable.
BA1
No population data was found for this allele in gnomAD (gnomAD v2.1.1).
BP5
Not applicable.
BP7
Intronic variant. Not applicable.
BP2
Not identified in individuals with other variants.
BP3
Not applicable.
BP4
PVS1 is met, not applicable.
BP1
Not applicable.
BS4
No non-segregations were identified/found.
BS3
No functional study showing no damaging effect on protein function or splicing.
BS1
No population data was found for this allele in gnomAD (gnomAD v2.1.1).
BS2
No unaffected family members were tested.
PP3
PVS1 is met, not applicable.
PP2
Not applicable.
Approved on: 2021-06-18
Published on: 2021-06-24
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