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.1586+5G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA035154

251909 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a4ff19d9-24d6-4f2e-961f-59d12a1eb75c

Approved on: 2024-02-23

Published on: 2024-12-02

HGVS expressions

NM_000527.5:c.1586+5G>A

NM_000527.5(LDLR):c.1586+5G>A

NC_000019.10:g.11113767G>A

CM000681.2:g.11113767G>A

NC_000019.9:g.11224443G>A

CM000681.1:g.11224443G>A

NC_000019.8:g.11085443G>A

NG_009060.1:g.29387G>A

ENST00000252444.10:c.1844+5G>A

ENST00000559340.2:c.1586+5G>A

ENST00000560467.2:c.1466+5G>A

ENST00000558518.6:c.1586+5G>A

ENST00000252444.9:c.1840+5G>A

ENST00000455727.6:c.1082+5G>A

ENST00000535915.5:c.1463+5G>A

ENST00000545707.5:c.1205+5G>A

ENST00000557933.5:c.1586+5G>A

ENST00000558013.5:c.1586+5G>A

ENST00000558518.5:c.1586+5G>A

ENST00000559340.1:c.307+5G>A

NM_000527.4:c.1586+5G>A

NM_001195798.1:c.1586+5G>A

NM_001195799.1:c.1463+5G>A

NM_001195800.1:c.1082+5G>A

NM_001195803.1:c.1205+5G>A

NM_001195798.2:c.1586+5G>A

NM_001195799.2:c.1463+5G>A

NM_001195800.2:c.1082+5G>A

NM_001195803.2:c.1205+5G>A

Uncertain Significance

PS3_Moderate

PM1 PM4 PM5 PM3 PM6 PM2 PVS1 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP3 BP4 BP1 PS1 PS2 PS4 PP4 PP1 PP3 PP2

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

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1586+5G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PS3_Moderate as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PS3_Moderate: -Level 2, PMID 10668928 (Jensen et al., 1999), heterologous cells (COS-7), FACS and CLSM assays, mutant protein retained at ER; <2% LDLR at surface, 2-5% LDL uptake. Overall LDLR activity is below 70% of wild-type activity. -Level 3, PMID 19208450 (Holla et al., 2009), heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays showed skipping of exon 10 (p.Thr454_Gly529del). -Level 3, PMID 10668928 (Jensen et al., 1999), heterozygous patients' Epstein Barr virus transformed lymphocytes, quantitative RT-PCR assays. Mutated transcripts were 47% of total transcripts; from mutated allele: 50% correctly spliced RNA, skipping of exon 10 (p.Thr454_Gly529del) in 25% of RNAs and retention of the first 66 nucleotides from intron 10 (p.Gly529_Phe530insCysValSerThrThrLeuArgAlaAlaGluGlyMetGluGlyAlaGlyArgSerPheArgAsnCys) in 25% of RNAs.

PS3_Moderate

Level 2, PMID 10668928: - Heterologous cells (COS-7), FACS and CLSM assays - Results: mutant protein retained at ER; <2% LDLR at surface, 2-5% LDL uptake ---- Overall LDLR activity is below 70% of wild-type activity. Level 3, PMID 19208450: - Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays. - Results: skipping of exon 10 (p.Thr454_Gly529del) Level 3, PMID 10668928: - Heterozygous patients' Epstein Barr virus transformed lymphocytes, quantitative RT-PCR assays - Results: Mutated transcripts are 47% of total transcripts; from mutated allele: 50% correctly spliced RNA, skipping of exon 10 (p.Thr454_Gly529del) in 25% of RNAs and retention of the first 66 nucleotides from intron 10 (p.Gly529_Phe530insCysValSerThrThrLeuArgAlaAlaGluGlyMetGluGlyAlaGlyArgSerPheArgAsnCys) in 25% of RNAs;

PM1

Not applicable

PM4

Not applicable

PM5

Not applicable

PM3

LDL-C value = 428, which is below 500 mg/dl

PM6

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

PM2

Popmax MAF = 0.0001962 (0.01962%) in South Asian exomes (gnomAD v2.1.1), and 0.0003023 (0.03023%) in South Asian exomes (gnomAD v4).

PVS1

Not applicable

BA1

FAF = 0.00008517 is South Asian exomes (gnomAD v2.1.1).

BS2

Variant not identified in normo-lipidemic adults

BS4

Segregation data unavailable

BS3

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

BS1

FAF = 0.00008517 is South Asian exomes (gnomAD v2.1.1).

BP5

Not applicable

BP7

Not applicable

BP3

Not applicable

BP4

Variant is an intronic variant

BP1

Not applicable

PS1

Not applicable

PS2

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

PS4

Variant is identified in 5 unrelated cases: - From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), 3 index cases with DLCN >= 6 - From Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 index case with SB possible for FH - From Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, 1 index case with DLCN >= 6 However, variant does not meet PM2, so PS4 is not met

PP4

Variant is identified in 5 FH cases: - From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), 3 cases with DLCN >= 6 - From Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 1 case with SB possible for FH - From Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, 1 case with DLCN >= 6 However, variant does not meet PM2, so PP4 is not met

PP1

Segregation data unavailable

PP3

Variant is an intronic variant

PP2

Not applicable

Curation History

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