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.47T>C (p.Leu16Pro)

CA10584733

250982 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ff62d848-368c-461c-8302-bd5947b0f8e7

HGVS expressions

NM_000527.5:c.47T>C
NM_000527.5(LDLR):c.47T>C (p.Leu16Pro)
NC_000019.10:g.11089595T>C
CM000681.2:g.11089595T>C
NC_000019.9:g.11200271T>C
CM000681.1:g.11200271T>C
NC_000019.8:g.11061271T>C
NG_009060.1:g.5215T>C
ENST00000558518.6:c.47T>C
ENST00000455727.6:c.47T>C
ENST00000535915.5:c.47T>C
ENST00000545707.5:c.47T>C
ENST00000557933.5:c.47T>C
ENST00000557958.1:n.133T>C
ENST00000558013.5:c.47T>C
ENST00000558518.5:c.47T>C
ENST00000560502.5:n.133T>C
NM_000527.4:c.47T>C
NM_001195798.1:c.47T>C
NM_001195799.1:c.47T>C
NM_001195800.1:c.47T>C
NM_001195803.1:c.47T>C
NM_001195798.2:c.47T>C
NM_001195799.2:c.47T>C
NM_001195800.2:c.47T>C
NM_001195803.2:c.47T>C
NR_163945.1:n.65A>G

Uncertain Significance

Met criteria codes 3
PS4_Supporting PP4 PM2
Not Met criteria codes 18
BS4 BS3 BS1 BP2 BP3 BP4 PVS1 PS2 PS3 PS1 PP1 PP3 PM6 PM3 PM1 PM4 PM5 BA1

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.47T>C (p.Leu16Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, PM2, and PP4 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: PM2: This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases, as follows: 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN criteria =9 (>6) from PMID 33668494 (Sabatel-Pérez et al, 2021). So PS4_Supporting is met. PP4: Variant meets PM2. Identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4_Supporting for details). So PP4 is met.
Met criteria codes
PS4_Supporting
Variant meets PM2 and is identified in 2 unrelated index cases, as follows: 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN criteria =9 (>6) from PMID 33668494 (Sabatel-Pérez et al, 2021). So PS4_Supporting is met.
PP4
Variant meets PM2. Identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4_Supporting for details). So PP4 is met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1.). So PM2 is met.
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
This variant is absent from gnomAD (gnomAD v2.1.1.).
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
REVEL is 0.674. It is >0.5, so BP4 is not met
PVS1
Not a null variant
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL is 0.674. It is <0.75. Splicing prediction is required: cenario A, Acceptor site: The variant is not located at -20 to +3 bases of canonical acceptor splicing site of any exons. Scenario A, Donor site: The variant is not located at -3 to +6 bases of canonical donor splicing site of any exons. Scenario B, Acceptor site: The variant is out of range. No need to studying denovo AG site. Scenario B, Donor site: The variant is located within the range but does not create denovo GT site. Scenario C, Acceptor site: The variant is out of range. No need to studying nearby AG site. Scenario C, Donor site: The variant is within the range and does not create a denovo GT. There is no GT in downstream (3 Nt) or upstream (6 Nt). Interpretation: The variant does not affect splicing process. So PP3 is not met
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
One other missense variant in the same codon: NM_000527.5(LDLR):c.46C>G (p.Leu16Val) (ClinVar ID 919564) Uncertain significance by these guidelines
BA1
This variant is absent from gnomAD (gnomAD v2.1.1.).
Approved on: 2022-08-29
Published on: 2022-12-23
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