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.2296A>G (p.Thr766Ala)

CA10585815

252267 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: c45bbab7-64ba-4043-87e2-c0bfbd706689
Approved on: 2024-10-28
Published on: 2025-01-20

HGVS expressions

NM_000527.5:c.2296A>G
NM_000527.5(LDLR):c.2296A>G (p.Thr766Ala)
NC_000019.10:g.11123329A>G
CM000681.2:g.11123329A>G
NC_000019.9:g.11234005A>G
CM000681.1:g.11234005A>G
NC_000019.8:g.11095005A>G
NG_009060.1:g.38949A>G
ENST00000252444.10:c.2554A>G
ENST00000559340.2:c.*365A>G
ENST00000560467.2:c.2176A>G
ENST00000558518.6:c.2296A>G
ENST00000252444.9:c.2550A>G
ENST00000455727.6:c.1792A>G
ENST00000535915.5:c.2173A>G
ENST00000545707.5:c.1762A>G
ENST00000557933.5:c.2296A>G
ENST00000558013.5:c.2296A>G
ENST00000558518.5:c.2296A>G
NM_000527.4:c.2296A>G
NM_001195798.1:c.2296A>G
NM_001195799.1:c.2173A>G
NM_001195800.1:c.1792A>G
NM_001195803.1:c.1762A>G
NM_001195798.2:c.2296A>G
NM_001195799.2:c.2173A>G
NM_001195800.2:c.1792A>G
NM_001195803.2:c.1762A>G
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Uncertain Significance

Met criteria codes 3
BP4 PP4 PM2
Not Met criteria codes 20
BA1 BS4 BS3 BS1 BS2 BP7 BP2 BP3 PS4 PS2 PS3 PS1 PP1 PP3 PM3 PM1 PM4 PM5 PM6 PVS1

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.2296A>G (p.Thr766Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4 and BP4 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= 0.00001600 (0.0016%) in Remaining group exomes (gnomAD v4.1.0). BP4: REVEL=0.481. it is below 0.50, splicing evaluation required. 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 = -26.75, wt cryptic = -35.70, canonical donor = 9.06. Scores are negative, splice site not used. Variant is not predicted to alter splicing. PP4: Variant meets PM2 and is identified in 1 case who fulfills Simon Broome criteria for possible FH after alternative causes of high cholesterol excluded, in PMID 20236128 (Taylor et al., 2010), UK.
Met criteria codes
BP4
REVEL=0.481. it is below 0.50, splicing evaluation required. 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 = -26.75, wt cryptic = -35.70, canonical donor = 9.06. Ratio variant cryptic/wt cryptic: 0.74 --- it is not above 1.1 Ratio variant cryptic/canonical donor: -2.95--- it is not above 0.9 Variant is not predicted to alter splicing. So, BP4 is met.
PP4
Variant meet PM2. PMID: 20236128 (Taylor et al., 2010), UK - 1 case who fulfills Simon Broome criteria for possible FH after alternative causes of high cholesterol were excluded. So, PP4 is met.
PM2
PopMax MAF= 0.00001600 (0.0016%) in Remaining group exomes (gnomAD v4.1.0). So, PM2 is met.
Not Met criteria codes
BA1
This variant is absent from gnomAD (gnomAD v4.1.0).
BS4
No data available.
BS3
No data available.
BS1
This variant is absent from gnomAD (gnomAD v4.1.0).
BS2
No data available.
BP7
Not a synonymous (silent) variant
BP2
No data available.
BP3
No in-frame deletions/insertions
PS4
Variant meet PM2. PMID: 20236128 (Taylor et al., 2010), UK - 1 case who fulfills Simon Broome criteria for possible FH
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No data available.
PS1
No other variant with the same amino acid change.
PP1
No data available.
PP3
REVEL=0.481. it is not above 0.75, splicing evaluation required. 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 = -26.75, wt cryptic = -35.70, canonical donor = 9.06. Scores are negative, splice site not used Variant is not predicted to alter splicing.
PM3
No data available.
PM1
Not on exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
PM5
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2297C>T (p.Thr766Ile) (ClinVar ID 252269) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
Not a null variant
Curation History
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