Evidence Repository - Clinical Genome Resources

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

Variant: NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023765

161287 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: da36a90c-1718-424e-83fa-5e42e5af70fa

Approved on: 2021-06-07

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.798T>A

NM_000527.5(LDLR):c.798T>A (p.Asp266Glu)

ENST00000558518.6:c.798T>A

ENST00000252444.9:n.1052T>A

ENST00000455727.6:c.314-724T>A

ENST00000535915.5:c.675T>A

ENST00000545707.5:c.417T>A

ENST00000557933.5:c.798T>A

ENST00000558013.5:c.798T>A

ENST00000558518.5:c.798T>A

ENST00000558528.1:n.313T>A

ENST00000560467.1:n.398T>A

NM_000527.4:c.798T>A

NM_001195798.1:c.798T>A

NM_001195799.1:c.675T>A

NM_001195800.1:c.314-724T>A

NM_001195803.1:c.417T>A

NM_001195798.2:c.798T>A

NM_001195799.2:c.675T>A

NM_001195800.2:c.314-724T>A

NM_001195803.2:c.417T>A

NC_000019.10:g.11106668T>A

CM000681.2:g.11106668T>A

NC_000019.9:g.11217344T>A

CM000681.1:g.11217344T>A

NC_000019.8:g.11078344T>A

NG_009060.1:g.22288T>A

Pathogenic

PM5_Strong PS4 PP4 PM2 PP1_Strong PS3_Moderate

BS3 BS1 BS4 BS2 BP5 BP7 BP4 BP1 BP2 BP3 PVS1 PS2 PS1 BA1 PP3 PP2 PM6 PM3 PM4 PM1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS4, PP1_Strong, PM5_Strong, PM2, PS3_Moderate and PP4) 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: PS4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. PP1_strong - variant segregates with phenotype in over 30 informative meiosis in several families from different laboratories. PM5_strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is met. PM2 - PopMax MAF = 0.00007740 (0.008%) in european non-finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) ---- Overall LDLR activity is below 70% of wild-type activity, so PS3_moderate is Met. PP4 - Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis.

PM5_Strong

Four more missense variants described in same codon: (1)NM_000527.5(LDLR):c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - classified as Pathogenic by these guidelines. (2)NM_000527.5(LDLR):c.796G>A (p.Asp266Asn) (ClinVar ID 226334) - classified as Pathogenic by these guidelines. (3)NM_000527.5(LDLR):c.797A>T (p.Asp266Val) (ClinVar ID 251458) - classified as Likely pathogenic by these guidelines. (4)NM_000527.5(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - classified as Pathogenic by these guidelines --- 3 variants classified as Pathogenic, so PM5_Strong is met

PS4

Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. --- PS4 is Met

PP4

Variant meets PM2. Identified in over 10 unrelated index cases from Center of molecular biology and gene therapy with FH diagnosis. ---- PP4 is Met

PM2

PopMax MAF = 0.00007740 (0.008%) in european non-finnish exomes (gnomAD v2.1.1). FAF is under 0.02%, so PM2 is Met.

PP1_Strong

variant segregates with phenotype in over 30 informative meiosis in several families from different laboratories (Center of molecular biology and gene therapy, GeneDx Inc. and GeneDx Inc.): 39 affected family members have the variant. --- PP1_Strong is Met

PS3_Moderate

Level 2 assay: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) ---- Overall LDLR activity is below 70% of wild-type activity, so PS3_moderate is Met

BS3

Level 3(benign) assays: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 15-30% LDLR activity (but all cycle was tested) ---- Results are not above 95% of activity, so BS3_supporting Not Met

BS1

FAF = 0.00003418 (0.0034%) in european non-finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

BS4

Variant does not segregate with phenotype in 1 informative meiosis from 1 family from Center of molecular biology and gene therapy: 1 affected family member does not have the variant. there is not enough evidence to meet BS4 --- BS4 is Not Met

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

BP4

REVEL = 0.739. It is not below 0.15, BP4 is Not Met

BP1

Not applicable

BP2

Variant identified in 4 index cases from Center of molecular biology and gene therapy with other LDLR variants - in 1 phenotype is of Homozygous FH - in 3 phenotype does not confirm or exclude homozygous FH. in all the 2nd variant is not specified, so BP2 is Not Met

BP3

Not applicable

PVS1

Missense variant, PVS1 Not Met

PS2

no de novo cases were identified, so PS2 is Not Met

PS1

No variant described that leads to the same amino acid change, so PS1 is Not Met

BA1

FAF = 0.00003418 (0.0034%) in european non-finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

PP3

REVEL = 0.739. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site, but it does not create GT. C) there is no GT nearby. No splicing prediction is applicable, so PP3 is Not Met

PP2

Not applicable

PM6

no de novo cases were identified, so PM6 is Not Met

PM3

Identified in 4 index cases from Center of molecular biology and gene therapy with other LDLR variants - in 1 phenotype is of Homozygous FH - in 3 phenotype does not confirm or exclude homozygous FH. in all the 2nd variant is not specified, so PM3 is Not Met

PM4

Missense variant, not applicable

PM1

Missense at codon 266. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

Curation History

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