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.2106G>A (p.Met702Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA038604

328053 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: feec542d-35d3-43de-8a46-151614a8b722

Approved on: 2024-08-30

Published on: 2024-10-03

HGVS expressions

NM_000527.5:c.2106G>A

NM_000527.5(LDLR):c.2106G>A (p.Met702Ile)

NC_000019.10:g.11120488G>A

CM000681.2:g.11120488G>A

NC_000019.9:g.11231164G>A

CM000681.1:g.11231164G>A

NC_000019.8:g.11092164G>A

NG_009060.1:g.36108G>A

ENST00000252444.10:c.2364G>A

ENST00000559340.2:c.*175G>A

ENST00000560467.2:c.1986G>A

ENST00000558518.6:c.2106G>A

ENST00000252444.9:c.2360G>A

ENST00000455727.6:c.1602G>A

ENST00000535915.5:c.1983G>A

ENST00000545707.5:c.1606+255G>A

ENST00000557933.5:c.2106G>A

ENST00000558013.5:c.2106G>A

ENST00000558518.5:c.2106G>A

NM_000527.4:c.2106G>A

NM_001195798.1:c.2106G>A

NM_001195799.1:c.1983G>A

NM_001195800.1:c.1602G>A

NM_001195803.1:c.1606+255G>A

NM_001195798.2:c.2106G>A

NM_001195799.2:c.1983G>A

NM_001195800.2:c.1602G>A

NM_001195803.2:c.1606+255G>A

Uncertain Significance

BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS4 PS3 PS1 BA1 PP1 PP4 PP3 PP2 PM6 PM2 PM3 PM1 PM4 PM5

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.2106G>A (p.Met702Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia as no ACMG/AMP evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on August 30, 2024.

BS4

no family members tested

BS3

no published functional studies

BS1

FAF = 0.000008030 (0.0008030%) in European non-Finnish exome+genomes (gnomAD v4.1.0). It is not above 0.2%, so BS1 is not met

BS2

not identified in normolipidemic individuals

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

not identified in individuals with more than 1 variant

BP3

not applicable

BP4

REVEL = 0.501. It is not below 0.50 so BP4 is not met

BP1

not applicable

PVS1

variant is missense and not in exon 1, so not applicable

PS2

no de novo occurrence

PS4

Variant does not meet PM2. Identified in 2 index cases fulfilling validated clinical criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN criteria ≥6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, CGMC-UFGOD APHP (GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix), France). But since it does not meet PM2, PS4 is not met

PS3

no published functional studies

PS1

There is one other variant in same codon: NM_000527.5(LDLR):c.2106G>C (p.Met702Ile), which is classified as Uncertain significance by these guidelines, so PS1 is not met

BA1

FAF = 0.000008030 (0.0008030%) in European non-Finnish exome+genomes (gnomAD v4.1.0). It is not above 0.5%, so BA1 is not met

PP1

no family members tested

PP4

PP3

REVEL = 0.501, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. A) Variant not on limits B) variant is exonic and at least 50 bp downstream from the canonical acceptor site, but it does not create GT. Therefore, this variant is not predicted to alter splicing, so PP3 is not met

PP2

not applicable

PM6

no de novo occurrence

PM2

PopMax MAF = 0.002567 (0.2567%) in Ashkenazi Jewish exomes+genomes (gnomAD v4.1.0). MAF is >0.02%, so PM2 is not met.

PM3

not identified in individuals with more than 1 variant

PM1

variant is missense, but does not meet PM2, is not in exon 4 and does not alter Cys, so not met

PM4

variant is missense, so not applicable

PM5

There is one other variant in same codon, but leads to the same amino acid change, so PM5 is not met

Curation History

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