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.1845G>A (p.Glu615=)

CA500025

252065 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: a90b351c-b5af-4371-9975-29978dc4247e
Approved on: 2022-08-29
Published on: 2022-12-23

HGVS expressions

NM_000527.5:c.1845G>A
NM_000527.5(LDLR):c.1845G>A (p.Glu615=)
NC_000019.10:g.11116998G>A
CM000681.2:g.11116998G>A
NC_000019.9:g.11227674G>A
CM000681.1:g.11227674G>A
NC_000019.8:g.11088674G>A
NG_009060.1:g.32618G>A
ENST00000558518.6:c.1845G>A
ENST00000252444.9:n.2099G>A
ENST00000455727.6:c.1341G>A
ENST00000535915.5:c.1722G>A
ENST00000545707.5:c.1464G>A
ENST00000557933.5:c.1845G>A
ENST00000558013.5:c.1845G>A
ENST00000558518.5:c.1845G>A
ENST00000559340.1:n.426+786G>A
NM_000527.4:c.1845G>A
NM_001195798.1:c.1845G>A
NM_001195799.1:c.1722G>A
NM_001195800.1:c.1341G>A
NM_001195803.1:c.1464G>A
NM_001195798.2:c.1845G>A
NM_001195799.2:c.1722G>A
NM_001195800.2:c.1341G>A
NM_001195803.2:c.1464G>A
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Uncertain Significance

Met criteria codes 3
PP4 PP3 PM2
Not Met criteria codes 8
PS3 PM4 PVS1 BA1 BS3 BS1 BP3 BP4

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.1845G>A (p.Glu615=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, 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: The only >10,000 subpopulation is European (Non-Finnish), in which the variant is absent. So PM2 is met. PP3: No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = -1.8; canonical donor wt = 4.48. Ratio: -1.8/4.48 = -0.4 ---- It is below 0.8. Variant is predicted to alter splicing. So PP3 is met. PP4: Variant meets PM2 and is identified in 1 case fulfilling Simon-Broome criteria for possible FH published in PMID: 17539906 (Taylor et al., 2007). So PP4 is met.
Met criteria codes
PP4
Variant meets PM2 and is identified in 1 case fulfilling Simon-Broome criteria for possible FH published in PMID: 17539906 (Taylor et al., 2007). So PP4 is met.
PP3
No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = -1.8; canonical donor wt = 4.48. Ratio: -1.8/4.48 = -0.4 ---- It is below 0.8. Variant is predicted to alter splicing. So PP3 is met.
PM2
The only >10,000 subpopulation is European (Non-Finnish), in which the variant is absent. So PM2 is met.
Not Met criteria codes
PS3
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
PVS1
Not a null variant
BA1
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
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
No REVEL, splicing evaluation required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = -1.8; canonical donor wt = 4.48. Ratio: -1.8/4.48 = -0.4 ---- It is below 0.8. Variant is predicted to alter splicing.
Curation History
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