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.1529C>T (p.Thr510Met)

CA034662

251886 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: a390335a-4f0a-438d-ba92-1626cdf8fc21
Approved on: 2024-08-30
Published on: 2024-10-03

HGVS expressions

NM_000527.5:c.1529C>T
NM_000527.5(LDLR):c.1529C>T (p.Thr510Met)
NC_000019.10:g.11113705C>T
CM000681.2:g.11113705C>T
NC_000019.9:g.11224381C>T
CM000681.1:g.11224381C>T
NC_000019.8:g.11085381C>T
NG_009060.1:g.29325C>T
ENST00000252444.10:c.1787C>T
ENST00000559340.2:c.1529C>T
ENST00000560467.2:c.1409C>T
ENST00000558518.6:c.1529C>T
ENST00000252444.9:c.1783C>T
ENST00000455727.6:c.1025C>T
ENST00000535915.5:c.1406C>T
ENST00000545707.5:c.1148C>T
ENST00000557933.5:c.1529C>T
ENST00000558013.5:c.1529C>T
ENST00000558518.5:c.1529C>T
ENST00000559340.1:c.250C>T
NM_000527.4:c.1529C>T
NM_001195798.1:c.1529C>T
NM_001195799.1:c.1406C>T
NM_001195800.1:c.1025C>T
NM_001195803.1:c.1148C>T
NM_001195798.2:c.1529C>T
NM_001195799.2:c.1406C>T
NM_001195800.2:c.1025C>T
NM_001195803.2:c.1148C>T

Uncertain Significance

Met criteria codes 4
PM2 PS4_Supporting PP4 PP3
Not Met criteria codes 22
PM6 PM3 PM1 PM4 PM5 BA1 PVS1 BS4 BS3 BS1 BS2 PS2 PS3 PS1 BP5 BP7 BP2 BP3 BP4 BP1 PP1 PP2

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.1529C>T (p.Thr510Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002228 (0.002228%) in East Asian exomes (gnomAD v4.1.0). PP3 - REVEL = 0.85. PS4_supporting, PP4: Variant meets PM2 and was identified in 4 unrelated index cases (1 case with DLCN score >=6 from Robarts Research Institute, Canada; 1 case meeting Simon Broome criteria from PMID 10947889 (Tonstad et al., 2000), Norway; 1 case with possible FH by MedPed criteria from PMID 22698793 (Tichý et al., 2012), Czech Republic; 1 case with clinical diagnosis of definite FH, probable FH or severe hypercholesterolemia according to the Canadian definition of FH from PMID 37607748 (Guerin et al., 2023), Canada].
Met criteria codes
PM2
PopMax MAF = 0.00002228 (0.002228%) in East Asian exomes (gnomAD v4.1.0). PopMax MAF is ≤0.02%, so PM2 is met.
PS4_Supporting
variant meets PM2 and was identified in 4 unrelated index cases [1 index case with DLCN criteria>=6 from Robarts Research Institute, Canada; 1 case with Simon Broome score of possible or definitive FH from PMID: 10947889 (Tonstad et al., 2000), Norway; 1 case with MedPed criteria of possible FH from PMID: 22698793 (Tichý et al., 2012), Czech Republic; 1 case with clinical diagnosis of definite FH, probable FH or severe hypercholesterolemia according to the Canadian definition of FH from PMID: 37607748 (Guerin et al., 2023), Canada].
PP4
Variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded.
PP3
PP3 - REVEL = 0.85. It is above 0.75, so PP3 is met
Not Met criteria codes
PM6
no de novo occurrence
PM3
Variant identified in two unrelated individuals with a second pathogenic variant (PMID: 16542394). Authors speculate both variants were in the same allele, although zygosity was not confirmed. Phenotype LDL-c ≤350 mg/dL - Htz phenotype. zygosity was not confirmed~, so not met
PM1
variant is missense and meets PM2, but is not in exon 4 and does not alter Cys
PM4
variant is missense, so not met
PM5
There are no other missense variants in the same codon
BA1
FAF = 0.000007630 (0.000763%) in European non-Finnish exomes+genomes (gnomAD v4.1.0). It is not above 0.5%, so not met
PVS1
variant is missense and not in initiation codon, so not met
BS4
no family members tested
BS3
no published functional studies
BS1
FAF = 0.000007630 (0.000763%) in European non-Finnish exomes+genomes (gnomAD v4.1.0). It is not above 0.2%, so not met
BS2
not identified in normolipidemic individuals
PS2
no de novo occurrence
PS3
no published functional studies
PS1
There are no other missense variants in the same codon
BP5
not applicable
BP7
variant is missense, so not met
BP2
Variant identified in two unrelated individuals with a second pathogenic variant (PMID: 16542394). Authors speculate both variants were in the same allele, although zygosity was not confirmed. Phenotype LDL-c ≤350 mg/dL - Htz phenotype. zygosity was not confirmed~, so not met
BP3
not aplicable
BP4
PP3 - REVEL = 0.85. It is not below 0.50, so BP4 is not met
BP1
not applicable
PP1
no family members tested
PP2
not applicable
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