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
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.1749C>A (p.His583Gln)

CA10585596

252014 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 295fc36b-5d7c-4f30-bf9c-8e36ef2a340b
Approved on: 2023-11-07
Published on: 2024-12-24

HGVS expressions

NM_000527.5:c.1749C>A
NM_000527.5(LDLR):c.1749C>A (p.His583Gln)
NC_000019.10:g.11116902C>A
CM000681.2:g.11116902C>A
NC_000019.9:g.11227578C>A
CM000681.1:g.11227578C>A
NC_000019.8:g.11088578C>A
NG_009060.1:g.32522C>A
ENST00000252444.10:c.2007C>A
ENST00000559340.2:c.1705+690C>A
ENST00000560467.2:c.1629C>A
ENST00000558518.6:c.1749C>A
ENST00000252444.9:c.2003C>A
ENST00000455727.6:c.1245C>A
ENST00000535915.5:c.1626C>A
ENST00000545707.5:c.1368C>A
ENST00000557933.5:c.1749C>A
ENST00000558013.5:c.1749C>A
ENST00000558518.5:c.1749C>A
ENST00000559340.1:c.426+690C>A
NM_000527.4:c.1749C>A
NM_001195798.1:c.1749C>A
NM_001195799.1:c.1626C>A
NM_001195800.1:c.1245C>A
NM_001195803.1:c.1368C>A
NM_001195798.2:c.1749C>A
NM_001195799.2:c.1626C>A
NM_001195800.2:c.1245C>A
NM_001195803.2:c.1368C>A
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Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM2 PM5
Not Met criteria codes 20
BS2 BS4 BS3 BS1 PS1 PS4 PS3 BP2 BP3 BP4 BP1 BP7 BP5 PP1 PP2 BA1 PVS1 PM3 PM4 PM1

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
NM_000527.5(LDLR):c.1749C>A (p.His583Gln) 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.805. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921). PP4: Variant meets PM2 and is identified in at least 1 index case with DLCN score >=6, after alternative causes of high cholesterol were excluded, from PMID 19318025 (Alonso et al., 2009).
Met criteria codes
PP4
Variant meets PM2 and is identified in at least 1 index case fulfilling DLCN criteria ≥ 6 for FH, after alternative causes of high cholesterol are excluded, from PMID: 19318025.
PP3
REVEL = 0.805. It is above 0.75, so PP3 is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
PM5
NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) (ClinVar ID: 200921) considered as pathogenic by these guidelines.
Not Met criteria codes
BS2
not met, (no information of index cases or report of segregation data/cases).
BS4
not met, (no information of index cases or report of segregation data/cases).
BS3
not met (no information or reports of functional data).
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
PS1
Another variant gives the same amino acid change, NM_000527.5(LDLR):c.1749C>G (p.His583Gln) (ClinVar ID: 441220), but is classified as uncertain significance by these guidelines.
PS4
not met, (no information of index cases or report of segregation data/cases).
PS3
not met (no information or reports of functional data).
BP2
Not identified in index cases with more than one variant
BP3
Missense variant, exon 12 - LDLR gene
BP4
REVEL = 0.805. It is not bellow 0.5, so BP4 is not met.
BP1
N/A according to FHVCEP guidelines
BP7
Missense variant, exon 12 - LDLR gene
BP5
N/A according to FHVCEP guidelines
PP1
not met, (no information of index cases or report of segregation data/cases).
PP2
N/A according to FHVCEP guidelines
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
PVS1
Missense variant, exon 12 - LDLR gene
PM3
Not identified in index cases with more than one variant
PM4
Missense variant, exon 12 - LDLR gene
PM1
Variant in exon 12 of the LDLR gene (not located at exon 4)
Curation History
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