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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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.2389+14G>A

CA9204959

252308 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 88632758-322d-4ebf-9ace-b19b2620da9f
Approved on: 2023-03-27
Published on: 2024-10-04

HGVS expressions

NM_000527.5:c.2389+14G>A
NM_000527.5(LDLR):c.2389+14G>A
NC_000019.10:g.11128099G>A
CM000681.2:g.11128099G>A
NC_000019.9:g.11238775G>A
CM000681.1:g.11238775G>A
NC_000019.8:g.11099775G>A
NG_009060.1:g.43719G>A
ENST00000252444.10:c.2647+14G>A
ENST00000559340.2:c.*458+14G>A
ENST00000560467.2:c.2269+14G>A
ENST00000558518.6:c.2389+14G>A
ENST00000252444.9:c.2643+14G>A
ENST00000455727.6:c.1885+14G>A
ENST00000535915.5:c.2266+14G>A
ENST00000545707.5:c.1855+14G>A
ENST00000557933.5:c.2389+14G>A
ENST00000558013.5:c.2389+14G>A
ENST00000558518.5:c.2389+14G>A
ENST00000560628.1:n.108+445G>A
NM_000527.4:c.2389+14G>A
NM_001195798.1:c.2389+14G>A
NM_001195799.1:c.2266+14G>A
NM_001195800.1:c.1885+14G>A
NM_001195803.1:c.1855+14G>A
NM_001195798.2:c.2389+14G>A
NM_001195799.2:c.2266+14G>A
NM_001195800.2:c.1885+14G>A
NM_001195803.2:c.1855+14G>A

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 25
PS2 PS4 PS3 PS1 BA1 PP1 PP4 PP3 PP2 PM6 PM2 PM3 PM1 PM4 PM5 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP1 PVS1

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.2389+14G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: BP4: No REVEL, splicing evaluation is required. Functional data on splicing not available. A) not within limits B) does not create GT C) not within limits Variant is not predicted to alter splicing.
Met criteria codes
BP4
No REVEL, splicing evaluation is required. Functional data on splicing not available. A) not within limits B) does not create GT C) not within limits Variant is not predicted to alter splicing.
Not Met criteria codes
PS2
No de novo cases were identified
PS4
variant does not meet PM2, so not met
PS3
No functional assays performed/found
PS1
Intronic variant - not applicable
BA1
FAF = 0.0003371 (0.032%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not ≥0.5%.
PP1
no family members tested
PP4
variant does not meet PM2, so not met
PP3
No REVEL, splicing evaluation is required. Functional data on splicing not available. A) not within limits B) does not create GT C) not within limits Variant is not predicted to alter splicing.
PP2
not applicable
PM6
No de novo cases were identified
PM2
PopMax MAF = 0.0005103 (0.05%) in Latino/Admixed American exomes+genomes (gnomAD v2.1.1). PopMax MAF is not ≤0.0002 and literature search does not suggest this is a well-known founder variant.
PM3
Variant identified in 2 index cases with other variants, both from Genomics Medicine Unit, Navarrabiomed, Spain: - index case 1 is also heterozygous for LPL c.1402A>G p.Lys468Glu and for APOE c.659C>T p.Pro220Leu and has Maximum LDL-c= 266mg/dl. Heterozygous phenotype, but other variants are not in LDLR, APOB nor PCSK9, so not met. - Index case 2 is also heterozygous for LDLR c.2054C>T p.Pro685Leu, classified as Pathogenic by these guidelines and had Maximum LDL-c= 195mg/dl. Heterozygous phenotype, but not tested if in cis or trans, so not met
PM1
Intronic variant - not applicable
PM4
Intronic variant - not applicable
PM5
Intronic variant - not applicable
BS4
no family members tested
BS3
No functional assays performed/found
BS1
FAF = 0.0003371 (0.032%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not ≥0.2%
BS2
Variant not identified in normolipidemic individuals
BP5
not applicable
BP7
Intronic variant - not applicable
BP2
Variant identified in 2 index cases with other variants, both from Genomics Medicine Unit, Navarrabiomed, Spain: - index case 1 is also heterozygous for LPL c.1402A>G p.Lys468Glu and for APOE c.659C>T p.Pro220Leu and has Maximum LDL-c= 266mg/dl. Heterozygous phenotype, but other variants are not in LDLR, APOB nor PCSK9, so not met. - Index case 2 is also heterozygous for LDLR c.2054C>T p.Pro685Leu, classified as Pathogenic by these guidelines and had Maximum LDL-c= 195mg/dl. Heterozygous phenotype, but not tested if in cis or trans, so not met
BP3
not applicable
BP1
not applicable
PVS1
Intronic variant, but not in canonical splicing region - not applicable
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