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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Variant: NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile)

CA023649

36461 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: cf5aea83-78f5-4c3c-8aaa-fb5df3b65938

HGVS expressions

NM_000527.5:c.2177C>T
NM_000527.5(LDLR):c.2177C>T (p.Thr726Ile)
NC_000019.10:g.11123210C>T
CM000681.2:g.11123210C>T
NC_000019.9:g.11233886C>T
CM000681.1:g.11233886C>T
NC_000019.8:g.11094886C>T
NG_009060.1:g.38830C>T
ENST00000558518.6:c.2177C>T
ENST00000252444.9:n.2431C>T
ENST00000455727.6:c.1673C>T
ENST00000535915.5:c.2054C>T
ENST00000545707.5:c.1643C>T
ENST00000557933.5:c.2177C>T
ENST00000558013.5:c.2177C>T
ENST00000558518.5:c.2177C>T
NM_000527.4:c.2177C>T
NM_001195798.1:c.2177C>T
NM_001195799.1:c.2054C>T
NM_001195800.1:c.1673C>T
NM_001195803.1:c.1643C>T
NM_001195798.2:c.2177C>T
NM_001195799.2:c.2054C>T
NM_001195800.2:c.1673C>T
NM_001195803.2:c.1643C>T

Benign

Met criteria codes 2
BP4 BA1
Not Met criteria codes 20
PVS1 BS2 BS4 BS3 BS1 BP7 BP2 PS2 PS1 PS3 PS4 PP3 PP1 PP4 PM6 PM2 PM1 PM3 PM4 PM5

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.2177C>T (p.Thr726Ile) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BA1 - FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met. BP4 - REVEL = 0.454, it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create AG C) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9 --- BP4 is Met.
Met criteria codes
BP4
REVEL = 0.454, it is below 0.50, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create AG C) variant is exonic and there 1 an AG nearby MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9 --- BP4 is Met.
BA1
FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BA1 is Met.
Not Met criteria codes
PVS1
Variant is not in canonical +/- 1,2 GT/AG splice site that predict a frameshift, so PVS1 is Not Met.
BS2
Not observed in 1000 normolipidemic individuals from Robarts Research Institute and in 200 non-FH alleles from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is Not Met.
BS4
Lack of segregation data not reported, so BS4 is Not Met.
BS3
Level 1 assays: PMID 34167030: Heterologous cells (CHO), FACS - result - Normal cell surface (91%), 86% LDL-LDLR binding and 96% uptake. ---- results are not above 90% of wild-type activity for the whole cycle (86% binding), so BS3 is not met.
BS1
FAF = 0.008138 (0.8138%) in European (non-Finnish) exomes (gnomAD v2.1.1), so BS1 is not met.
BP7
Variant is not synonymous, so BP7 is Not Met.
BP2
Variant identified in index cases with heterozygous FH phenotype and other LDLR variants, but cannot determine if these variants are in trans, so BP2 is not met.
PS2
de novo occurrence data not reported, so PS2 is Not Met.
PS1
No more missense variants at the same codon, so PS1 is Not Met.
PS3
Level 1 assays: PMID 34167030: Heterologous cells (CHO), FACS - result - Normal cell surface (91%), 86% LDL-LDLR binding and 96% uptake. ---- functional study is consistent with no damaging effect, so PS3 is not met.
PS4
Variant does not meet PM2, so PS4 is Not Met.
PP3
REVEL = 0.454, it is not above 0.75, so splicing evaluation is required. Functional data on splicing not available. A) variant not on limits B) does not create AG C) variant is exonic and there are 3 AG nearby 1) MES scores: variant cryptic = -1.90, wt cryptic = -1.77, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -1.90/-1.77 = 1.07 --- it is not above 1.1 Ratio variant cryptic/canonical acceptor: -1.90/8.76 --- it is not above 0.9 2) MES scores: variant cryptic = -8.77, wt cryptic = -3.45, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -8.77/-3.45 = 2.54 --- it is above 1.1 Ratio variant cryptic/canonical acceptor: -8.77/8.76 --- it is not above 0.9 3) MES scores: variant cryptic = -14.64, wt cryptic = -9.10, canonical acceptor = 8.76. Ratio variant cryptic/wt cryptic: -14.64/-9.10 = 1.61 --- it is above 1.1 Ratio variant cryptic/canonical acceptor: -14.647/8.76 --- it is not above 0.9 --- PP3 is not met.
PP1
Segregation data not reported, so PP1 is Not Met.
PP4
Variant does not meet PM2, so PP4 is Not Met.
PM6
de novo occurrence data not reported, so PM6 is Not Met.
PM2
PopMax MAF = 0.01123 (1.123%) in European (Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is not met.
PM1
Variant does not meet PM2. Also is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
PM3
Variant does not meet PM2, so PM3 is Not Met.
PM4
Variant does not meet PM2 and is not due to in-frame deletions/insertions, so PM4 is not met.
PM5
No more missense variants at the same codon, so PM5 is Not Met.
Approved on: 2022-05-24
Published on: 2022-12-24
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