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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data

Variant: NM_000527.5(LDLR):c.1414G>A (p.Asp472Asn)

CA404085864

633286 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 82f67562-6cbc-4292-a73d-229c83c1e24d
Approved on: 2025-01-31
Published on: 2025-02-27

HGVS expressions

NM_000527.5:c.1414G>A
NM_000527.5(LDLR):c.1414G>A (p.Asp472Asn)
NC_000019.10:g.11113590G>A
CM000681.2:g.11113590G>A
NC_000019.9:g.11224266G>A
CM000681.1:g.11224266G>A
NC_000019.8:g.11085266G>A
NG_009060.1:g.29210G>A
ENST00000252444.10:c.1672G>A
ENST00000559340.2:c.1414G>A
ENST00000560467.2:c.1294G>A
ENST00000558518.6:c.1414G>A
ENST00000252444.9:c.1668G>A
ENST00000455727.6:c.910G>A
ENST00000535915.5:c.1291G>A
ENST00000545707.5:c.1033G>A
ENST00000557933.5:c.1414G>A
ENST00000558013.5:c.1414G>A
ENST00000558518.5:c.1414G>A
ENST00000559340.1:c.135G>A
ENST00000560467.1:c.894G>A
NM_000527.4:c.1414G>A
NM_001195798.1:c.1414G>A
NM_001195799.1:c.1291G>A
NM_001195800.1:c.910G>A
NM_001195803.1:c.1033G>A
NM_001195798.2:c.1414G>A
NM_001195799.2:c.1291G>A
NM_001195800.2:c.910G>A
NM_001195803.2:c.1033G>A
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Uncertain Significance

Met criteria codes 4
PP4 PM2 PM5 BP4
Not Met criteria codes 5
PS3 PS4 PS1 PP3 BS3

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.1414G>A (p.Asp472Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP4 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001120 (0.0112%) in Remaining exomes+genomes (gnomAD v4.1.0); PM5 - 1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (ClinVar ID 183116) -Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines; BP4 - REVEL = 0.318, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create AG. Variant is not predicted to alter splicing; PP4 - Variant meets PM2. Identified in at least 1 index case fulfilling Japanese Atherosclerosis Society criteria for FH from PMID 36229376, after alternative causes of high cholesterol were excluded.
Met criteria codes
PP4
Variant meets PM2. PMID: 36229376 (Tada et al., 2022), Japan - 1 case who fulfills Japanese Atherosclerosis Society criteria for FH, after alternative causes of high cholesterol were excluded.
PM2
PopMax MAF = 0.0001120 (0.0112%) in Remaining exomes+genomes (gnomAD v4.1.0)
PM5
1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) (ClinVar ID 183116) -Pathogenic by these guidelines
BP4
REVEL = 0.318, it is below 0.50, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create AG Variant is not predicted to alter splicing
Not Met criteria codes
PS3
No functional assays performed/found - not applicable.
PS4
Variant meets PM2 but is only identified in 1 index case fulfilling Japanese Atherosclerosis Society (JAS) 2017 FH criteria from PMID 36229376.
PS1
1 other missense variant that leads to the same amino acid change: - NM_000527.5(LDLR):c.1413_1414delinsGA (p.Asp472Asn) (ClinVar ID 927821), but variant classified as of uncertain significance by these guidelines, so PS1 not met.
PP3
REVEL = 0.318. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant is not on limits. B) variant does not create AG/GT. C) there is an AG nearby. MES scores: variant cryptic site = 3.27, wt cryptic site = 2.79, canonical acceptor = 6.76. Ratio variant cryptic/wt cryptic score: 3.27/2.79 = 1.17 --- it is above 1.1 Ratio variant cryptic/canonical acceptor score: 3.27/6.76 = 0.48--- it is not above 0.9 ---PP3 is not met.
BS3
No functional assays performed/found - not applicable.
Curation History
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