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.2297C>T (p.Thr766Ile)

CA10585816

252269 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 91968271-d2f5-42ca-9704-7b8dafdd15fc
Approved on: 2024-10-28
Published on: 2025-01-20

HGVS expressions

NM_000527.5:c.2297C>T
NM_000527.5(LDLR):c.2297C>T (p.Thr766Ile)
NC_000019.10:g.11123330C>T
CM000681.2:g.11123330C>T
NC_000019.9:g.11234006C>T
CM000681.1:g.11234006C>T
NC_000019.8:g.11095006C>T
NG_009060.1:g.38950C>T
ENST00000252444.10:c.2555C>T
ENST00000559340.2:c.*366C>T
ENST00000560467.2:c.2177C>T
ENST00000558518.6:c.2297C>T
ENST00000252444.9:c.2551C>T
ENST00000455727.6:c.1793C>T
ENST00000535915.5:c.2174C>T
ENST00000545707.5:c.1763C>T
ENST00000557933.5:c.2297C>T
ENST00000558013.5:c.2297C>T
ENST00000558518.5:c.2297C>T
NM_000527.4:c.2297C>T
NM_001195798.1:c.2297C>T
NM_001195799.1:c.2174C>T
NM_001195800.1:c.1793C>T
NM_001195803.1:c.1763C>T
NM_001195798.2:c.2297C>T
NM_001195799.2:c.2174C>T
NM_001195800.2:c.1793C>T
NM_001195803.2:c.1763C>T
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Uncertain Significance

Met criteria codes 2
PP4 PM2
Not Met criteria codes 21
BS4 BS3 BS1 BS2 BP7 BP2 BP3 BP4 PVS1 PS1 PS2 PS4 PS3 BA1 PP1 PP3 PM6 PM5 PM3 PM1 PM4

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.2297C>T (p.Thr766Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0). PP4: Variant meets PM2 and is identified in one index case who fulfils DLCN criteria for probable FH after alternative causes of high cholesterol excluded, reported in PMID 16250003 (Fouchier et al., 2005), The Netherlands.
Met criteria codes
PP4
Variant meet PM2. PMID: 16250003 (Fouchier et al., 2005), Netherlands - 1 case who fulfills an internationally accepted criteria [Defesche, 2000] for FH after alternative causes of high cholesterol were excluded. So, PP4 is met.
PM2
PopMax MAF = 0.00001098 (0.001098%) in South Asian exomes (gnomAD v4.1.0). So, PM2 is met.
Not Met criteria codes
BS4
No data available
BS3
No data available.
BS1
FAF=0.000001368 (0.0001368 %) in South Asian exomes (gnomAD v4.1.0).
BS2
No data available.
BP7
Not a synonymous (silent) variant
BP2
No data available
BP3
No in-frame deletions/insertions
BP4
REVEL=0.59. It is above 0.5.
PVS1
Not a null variant
PS1
No other missense variant with the same amino acid change
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant meet PM2. PMID: 16250003 (Fouchier et al., 2005), Netherlands - 1 case who fulfills an internationally accepted criteria [Defesche, 2000] for FH
PS3
No data available.
BA1
FAF=0.000001368 (0.0001368 %) in South Asian exomes (gnomAD v4.1.0).
PP1
No data available
PP3
REVEL=0.59. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) there is a GT nearby. MES scores: variant cryptic = -31.51, wt cryptic = -27.00, canonical donor = 9.06. Scores are negative, splice site not used. Variant is not predicted to alter splicing.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2296A>G (p.Thr766Ala) (ClinVar ID 252267) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM3
No data available
PM1
Not on exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
Curation History
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