The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.261G>A (p.Trp87Ter)

CA10584814

251100 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
UUID: e7e3458e-bc95-482d-b7a2-3b7ab1a7d3e5
Approved on: 2021-06-07
Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.261G>A
NM_000527.5(LDLR):c.261G>A (p.Trp87Ter)
ENST00000558518.6:c.261G>A
ENST00000252444.9:n.515G>A
ENST00000455727.6:c.261G>A
ENST00000535915.5:c.190+2389G>A
ENST00000545707.5:c.261G>A
ENST00000557933.5:c.261G>A
ENST00000557958.1:n.347G>A
ENST00000558013.5:c.261G>A
ENST00000558518.5:c.261G>A
NM_000527.4:c.261G>A
NM_001195798.1:c.261G>A
NM_001195799.1:c.190+2389G>A
NM_001195800.1:c.261G>A
NM_001195803.1:c.261G>A
NM_001195798.2:c.261G>A
NM_001195799.2:c.190+2389G>A
NM_001195800.2:c.261G>A
NM_001195803.2:c.261G>A
NC_000019.10:g.11102734G>A
CM000681.2:g.11102734G>A
NC_000019.9:g.11213410G>A
CM000681.1:g.11213410G>A
NC_000019.8:g.11074410G>A
NG_009060.1:g.18354G>A
More

Pathogenic

Met criteria codes 5
PS3_Supporting PVS1 PM2 PS4 PP4
Not Met criteria codes 21
BS2 BS4 BS3 BS1 BP4 BP1 BP2 BP3 BP7 BP5 BA1 PM6 PM3 PM4 PM1 PM5 PS2 PS1 PP3 PP2 PP1

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.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met
Met criteria codes
PS3_Supporting
Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met
PVS1
Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met
PM2
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
PS4
Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. --- PS4 is Met
PP4
Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. --- PP4 is Met
Not Met criteria codes
BS2
no unaffected individuals identified with the variant, so BS2 is Not Met
BS4
no family members were tested, so BS4 is Not Met
BS3
Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Whole cycle is not above 95% of wild-type, so BS3_supporting is Not Met
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
BP4
PVS1 is Met, so BP4 is not applicable
BP1
Not applicable
BP2
not identified in individuals with other variants, so BP2 is Not Met
BP3
Not applicable
BP7
Nonsense variant, so BP7 is not applicable
BP5
Not applicable
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1).
PM6
no de novo cases were identified, so PM6 is Not Met
PM3
not identified in individuals with other variants, so PM3 is Not Met
PM4
Nonsense variant (PVS1 is Met), so PM4 is Not Met
PM1
Nonsense variant, so PM1 is Not applicable
PM5
Nonsense variant, PM5 not applicable
PS2
no de novo cases were identified, so PS2 is Not Met
PS1
Nonsense variant, PS1 not applicable
PP3
PVS1 is Met, so PP3 is not applicable
PP2
Not applicable
PP1
no family members were tested, so PP1 is Not Met
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.