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
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.1474G>C (p.Asp492His)

CA10585474

251864 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: 407b6edd-ffe7-4abe-9722-8d4bfc2c0ea1
Approved on: 2023-11-07
Published on: 2024-10-03

HGVS expressions

NM_000527.5:c.1474G>C
NM_000527.5(LDLR):c.1474G>C (p.Asp492His)
NC_000019.10:g.11113650G>C
CM000681.2:g.11113650G>C
NC_000019.9:g.11224326G>C
CM000681.1:g.11224326G>C
NC_000019.8:g.11085326G>C
NG_009060.1:g.29270G>C
ENST00000252444.10:c.1732G>C
ENST00000559340.2:c.1474G>C
ENST00000560467.2:c.1354G>C
ENST00000558518.6:c.1474G>C
ENST00000252444.9:c.1728G>C
ENST00000455727.6:c.970G>C
ENST00000535915.5:c.1351G>C
ENST00000545707.5:c.1093G>C
ENST00000557933.5:c.1474G>C
ENST00000558013.5:c.1474G>C
ENST00000558518.5:c.1474G>C
ENST00000559340.1:c.195G>C
NM_000527.4:c.1474G>C
NM_001195798.1:c.1474G>C
NM_001195799.1:c.1351G>C
NM_001195800.1:c.970G>C
NM_001195803.1:c.1093G>C
NM_001195798.2:c.1474G>C
NM_001195799.2:c.1351G>C
NM_001195800.2:c.970G>C
NM_001195803.2:c.1093G>C
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Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM2 PM5
Not Met criteria codes 1
PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5 (LDLR):c.1474G>C (p.Asp492His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00002 in Non-Finnish European population in gnomAD (gnomAD v2.1.1). PP3: REVEL=0.993. PM5: Two other missense variants in the same codon: NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn), ClinVar 161285, classified as Pathogenic by these guidelines; NM_000527.5(LDLR):c.1475A>G (p.Asp492Gly), ClinVar 251865, classified as Likely Pathogenic by these guidelines. Therefore PM5 is met. PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for FH diagnosis after alternative causes of high cholesterol were excluded, reported in PMID 10208479 (Heath et al., 1999), from University College London Medical School, UK.
Met criteria codes
PP4
Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for FH diagnosis after alternative causes of high cholesterol were excluded, reported in PMID 10208479 by Heath et al, 1999, from University College London Medical School, UK.
PP3
REVEL=0.993.
PM2
PopMax MAF=0.00002 in Non-Finnish European population in gnomAD (gnomAD v2.1.1).
PM5
Two other missense variants in the same codon: NM_000527.5(LDLR):c.1474G>A(p.Asp492Asn (ClinVarID 161285) classified as Pathogenic by these guidelines. NM_000527.5(LDLR):c.1475A>G(p.Asp492Gly) (ClinVarID 251865) classified as Likely Pathogenic by these guidelines. Therefore PM5 is met.
Not Met criteria codes
PS3
Functional data is not available.
Curation History
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