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]
Link to SEPIO compliant JSON-LD document
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR

Variant: NM_000527.4(LDLR):c.-136C>G

CA10584708

250954 (ClinVar)

Gene: N/A
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 4770813f-9133-4b63-ac53-f9147828a1f0

HGVS expressions

NM_000527.4(LDLR):c.-136C>G
NC_000019.10:g.11089413C>G
CM000681.2:g.11089413C>G
NC_000019.9:g.11200089C>G
CM000681.1:g.11200089C>G
NC_000019.8:g.11061089C>G
NG_009060.1:g.5033C>G
ENST00000558518.5:c.-136C>G
NM_000527.4:c.-136C>G
NM_001195798.1:c.-136C>G
NM_001195799.1:c.-136C>G
NM_001195800.1:c.-136C>G
NM_001195803.1:c.-136C>G
NR_163945.1:n.247G>C

Uncertain Significance

Met criteria codes 3
PP4 PM2 PS3_Moderate
Not Met criteria codes 23
PS2 PS4 PS1 PP1 PP3 PP2 PM6 PM3 PM1 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.4(LDLR):c.-136C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate 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. PS3_moderate - 2 Level 3 FS: (1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression (2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression --- in both studies, transcription levels are below 50% of wild-type, so PS3_Moderate is met. PP4 - Variant meets PM2 and is identified in 1 index case who fulfills DLCN >6 criteria for FH from PMID: 21538688, after alternative causes of high cholesterol were excluded.
Met criteria codes
PP4
Variant meets PM2 and is identified in 1 index case who fulfills DLCN >6 criteria for FH from PMID: 21538688, after alternative causes of high cholesterol were excluded.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.
PS3_Moderate
2 Level 3 FS: (1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression (2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression --- in both studies, transcription levels are below 50% of wild-type, so PS3_Moderate is met
Level 3: saturation mutagenesis in HepG2 cells, luciferase high throughput study: 16% and 11% luciferase expression PubMed:31395865
Not Met criteria codes
PS2
no de novo occurrence
PS4
Variant meets PM2 and is identified in 1 index case who fulfills DLCN >6 criteria for FH from PMID: 21538688, after alternative causes of high cholesterol were excluded. not enough
PS1
variant is in 5'UTR, so not applicable
PP1
no family data
PP3
variant is in 5'UTR, so not applicable
PP2
Not applicable
PM6
no de novo occurrence
PM3
not identified in cases with other variants
PM1
variant is in 5'UTR, so not applicable
PM4
variant is in 5'UTR, so not applicable
PM5
variant is in 5'UTR, so not applicable
PVS1
variant is in 5'UTR, so not applicable
BA1
This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met.
BS2
not identified in normolipidemic individuals, so not met
BS4
no family data
BS3
2 Level 3 FS: (1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression (2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression --- transcription levels are not above 90% of wild-type, so BS3_Supporting is not met
BS1
This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met.
BP2
not identified in cases with other variants
BP3
Not applicable
BP4
variant is in 5'UTR, so not applicable
BP1
Not applicable
BP5
not applicable
BP7
variant is in 5'UTR, so not applicable
Approved on: 2022-08-28
Published on: 2022-08-28
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