Evidence Repository - GenboreeKB

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.796G>A (p.Asp266Asn)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10576288

226334 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: febc36e7-3293-4e52-8666-7a907e25a4a9

Approved on: 2022-05-04

Published on: 2022-06-30

HGVS expressions

NM_000527.5:c.796G>A

NM_000527.5(LDLR):c.796G>A (p.Asp266Asn)

NC_000019.10:g.11106666G>A

CM000681.2:g.11106666G>A

NC_000019.9:g.11217342G>A

CM000681.1:g.11217342G>A

NC_000019.8:g.11078342G>A

NG_009060.1:g.22286G>A

ENST00000252444.10:c.1054G>A

ENST00000559340.2:c.796G>A

ENST00000560467.2:c.796G>A

ENST00000558518.6:c.796G>A

ENST00000252444.9:c.1050G>A

ENST00000455727.6:c.314-726G>A

ENST00000535915.5:c.673G>A

ENST00000545707.5:c.415G>A

ENST00000557933.5:c.796G>A

ENST00000558013.5:c.796G>A

ENST00000558518.5:c.796G>A

ENST00000558528.1:n.311G>A

ENST00000560467.1:c.396G>A

NM_000527.4:c.796G>A

NM_001195798.1:c.796G>A

NM_001195799.1:c.673G>A

NM_001195800.1:c.314-726G>A

NM_001195803.1:c.415G>A

NM_001195798.2:c.796G>A

NM_001195799.2:c.673G>A

NM_001195800.2:c.314-726G>A

NM_001195803.2:c.415G>A

Pathogenic

PS3_Moderate PS4 PM2 PP1 PP3 PP4 PM5_Strong

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

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. c.796G>A (p.Asp266Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM5_Strong, PS3_Moderate, PP1, PP3 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. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID: 12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory); PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1); PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines. PS3_Moderate - Level 2 assay: PMID 12414836: Homozygous patient cells, 125I assays - result - <2% LDL-LDLR binding and internalisation. Functional study is consistent with damaging effect; PP1 - 3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); PP3 - REVEL = 0,83; PP4 - Variant meets PM2. Identified in at least 1 FH case fulfilling Simon-Broome criteria published in PMID 12414836.

PS3_Moderate

Level 2 assays: PMID 12414836: Homozygous patient cells, I125 assays - result - <2% LDL-LDLR binding and internalisation (only results of binding and internalisation at 37°C are shown). ---- functional study is consistent with damaging effect

PS4

Variant meets PM2. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID: 12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory).

PM2

PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1).

PP1

3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)

PP3

REVEL = 0,83

PP4

PM5_Strong

4 other missense variants in the same codon: - NM_000527.5(LDLR):c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR):c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR):c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines.

BS1