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_000527.4(LDLR):c.-156C>T

CA10584696

250942 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: b26cdb00-be2b-49b3-b720-85d27e07d351

HGVS expressions

NM_000527.4:c.-156C>T
NM_000527.4(LDLR):c.-156C>T
NC_000019.10:g.11089393C>T
CM000681.2:g.11089393C>T
NC_000019.9:g.11200069C>T
CM000681.1:g.11200069C>T
NC_000019.8:g.11061069C>T
NG_009060.1:g.5013C>T
ENST00000558518.5:c.-156C>T
NM_001195798.1:c.-156C>T
NM_001195799.1:c.-156C>T
NM_001195800.1:c.-156C>T
NM_001195803.1:c.-156C>T
NR_163945.1:n.267G>A

Uncertain Significance

Met criteria codes 4
PS4_Supporting PP4 PS3_Supporting PM2
Not Met criteria codes 18
BS4 BS3 BS1 BS2 BP7 BP2 BP4 PVS1 PS2 PS1 PP1 PP3 PM6 PM5 PM3 PM1 PM4 BA1

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, 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). PS3_supporting - Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532). PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded.
Met criteria codes
PS4_Supporting
Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532), so PS4_Supporting is Met.
PP4
Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532), so PP4 is Met.
PS3_Supporting
Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect, so PS3_Supporting is Met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.
Not Met criteria codes
BS4
Segregation data without phenotype reported, so BS4 is Not Met.
BS3
Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect, so BS3 in Not Met.
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.
BS2
Case-control data not reported, so BS2 is Not Met.
BP7
Variant is not synonymous, so BP7 is Not Met.
BP2
Variant meets PM2 and is identified in 2 index cases with LDLR c.-156C>T, not classified as Pathogenic/Likely pathogenic by these guidelines; 1 index case from Ambry Lab with heterozygous FH phenotype (LDL=185 on medication) and other index case ( PMID: 14974088) with possible homozygous phenotype (LDL=377), so BP2 is not met.
BP4
Variant is on 5'UTR, so BP4 is Not Met.
PVS1
Variant is on 5'UTR, so PVS1 is Not Met.
PS2
de novo occurrence data not reported, so PS2 is Not Met.
PS1
Variant is not missense, so PS1 is Not Met.
PP1
Segregation data without phenotype reported, so PP1 is Not Met.
PP3
Variant is on 5'UTR, so PP3 is Not Met.
PM6
de novo occurrence data not reported, so PM6 is Not Met.
PM5
Variant is not missense, so PM5 is Not Met.
PM3
Variant meets PM2 and is identified in 3 index cases with LDLR c.-156C>T, not classified as Pathogenic/Likely pathogenic by these guidelines; 1 index case from Ambry Lab with heterozygous FH phenotype (LDL=185 on medication); 1 index case (PMID: 14974088) with possible homozygous phenotype (LDL=377); and other index case (PMID: 31947532) with homozygous phenotype (LDL >13 mmol/L), so PM3 is not met.
PM1
Variant meets PM2 but is not missense, so PM1 is Not Met.
PM4
Variant meets PM2 but is on 5'UTR, so PM4 is Not Met.
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.
Approved on: 2023-03-20
Published on: 2023-03-31
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