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]

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Variant: NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn)

CA354422

183128 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 553eb123-6677-44dd-acb4-b7cbdf6514e5

HGVS expressions

NM_000527.5:c.1951G>A

NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn)

NC_000019.10:g.11120197G>A

CM000681.2:g.11120197G>A

NC_000019.9:g.11230873G>A

CM000681.1:g.11230873G>A

NC_000019.8:g.11091873G>A

NG_009060.1:g.35817G>A

ENST00000558518.6:c.1951G>A

ENST00000252444.9:n.2205G>A

ENST00000455727.6:c.1447G>A

ENST00000535915.5:c.1828G>A

ENST00000545707.5:c.1570G>A

ENST00000557933.5:c.1951G>A

ENST00000558013.5:c.1951G>A

ENST00000558518.5:c.1951G>A

ENST00000559340.1:n.532G>A

NM_000527.4:c.1951G>A

NM_001195798.1:c.1951G>A

NM_001195799.1:c.1828G>A

NM_001195800.1:c.1447G>A

NM_001195803.1:c.1570G>A

NM_001195798.2:c.1951G>A

NM_001195799.2:c.1828G>A

NM_001195800.2:c.1447G>A

NM_001195803.2:c.1570G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4 PP1 PM2 PS4_Moderate

BP2 BP3 BP4 PS2 PS3 PS1 BA1 PP3 PM6 PM3 PM1 PM4 PM5 PVS1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

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_000527.5(LDLR):c.1951G>A (p.Asp651Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Moderate, PM2, PP1, 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: PS4_Moderate: Variant meets PM2 and is identified in 8 unrelated index cases (1 case with Simon-Broome criteria of possible FH and 1 case with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 2 cases with Simon-Broome criteria of possible FH and 1 case with DLCN>6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, and 3 cases in PMID 15241806 (Mozas P et al., 2004)). So PS4_Moderate is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So PM2 is met. PP1: Variant segregates with FH phenotype in 3 informative meioses identified by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So PP1 is met. PP4: Variant meets PM2 and is identified in2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.

PP4

Variant meets PM2 and is identified in2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met.

PP1

Variant segregates with FH phenotype in 3 informative meioses identified by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So PP1 is met.

PM2

PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So PM2 is met.

PS4_Moderate

Variant meets PM2 and is identified in 8 unrelated index cases (1 case with Simon-Broome criteria of possible FH and 1 case with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 2 cases with Simon-Broome criteria of possible FH and 1 case with DLCN>6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, and 3 cases in PMID 15241806 (Mozas P et al., 2004)). So PS4_Moderate is met.

BP2

Variant identified in an index case with FH phenotype and c.662A>G (p.Asp221Gly) variant, classified as Pathogenic by the general ACMG guidelines from PMID 29396260. The LDL-C level is 232 mg/dl. However, this participant is taking rosuvastatin 40 mg and ezetimibe. Based on 2019 ESC guidelines for the management of dyslipidemias, a combination of high-intensity statin and ezetimibe results in 65% reduction in LDL-C. So, the untreated LDL-C value would be around 663 mg/dl (homozygous FH phenotype).

BP3

Not a in-frame deletions/insertion variant

BP4

REVEL = 0.697. It is above 0.5, so BP4 is not met.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

No data available

PS1

No other missense variant in the same codon with the same amino acid change

BA1

No PopMax FAF available. PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).

PP3

REVEL = 0.697. It is not above 0.75, so splicing evaluation is required. Functional data on splicing is not available. A) variant is not located at -20 to +3 bases from canonical acceptor splice site/-3 to +6 from canonical donor splice site B) Variant is not on limits of acceptor site. It is located within the range of the donor site but does not create denovo GT site. C) Variant is not on limits of acceptor site. It is located within the range of the donor site but there is no GT in downstream or upstream. The variant does not affect splicing process.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Not located in exon 4. Not a cysteine residue.

PM4

Not a in-frame deletions/insertion variant

PM5

2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1951G>T (p.Asp651Tyr) (ClinVar ID 252127) - Likely Pathogenic by these guidelines - NM_000527.5(LDLR):c.1952A>T (p.Asp651Val) (ClinVar ID 252128) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PVS1

Not a null variant (nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion)

BS2

No data available

BS4

No data available

BS3

In vitro microscopy assays in HeLa cells: LDLR activity is equal to WT - considered as non-disruptive. It is a part of the LDLR cycle, so BS3 is not met.

BS1

No PopMax FAF available. PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1).

Approved on: 2023-03-20

Published on: 2023-03-31

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