Variant: NM_000527.5(LDLR):c.2125A>G (p.Arg709Gly)

CA16602347

375833 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 6001e07f-6fb5-4942-93be-26876d62a22d

Approved on: 2024-10-28

Published on: 2025-01-19

HGVS expressions

NM_000527.5:c.2125A>G
NM_000527.5(LDLR):c.2125A>G (p.Arg709Gly)
NC_000019.10:g.11120507A>G
CM000681.2:g.11120507A>G
NC_000019.9:g.11231183A>G
CM000681.1:g.11231183A>G
NC_000019.8:g.11092183A>G
NG_009060.1:g.36127A>G
ENST00000252444.10:c.2383A>G
ENST00000559340.2:c.*194A>G
ENST00000560467.2:c.2005A>G
ENST00000558518.6:c.2125A>G
ENST00000252444.9:c.2379A>G
ENST00000455727.6:c.1621A>G
ENST00000535915.5:c.2002A>G
ENST00000545707.5:c.1606+274A>G
ENST00000557933.5:c.2125A>G
ENST00000558013.5:c.2125A>G
ENST00000558518.5:c.2125A>G
NM_000527.4:c.2125A>G
NM_001195798.1:c.2125A>G
NM_001195799.1:c.2002A>G
NM_001195800.1:c.1621A>G
NM_001195803.1:c.1606+274A>G
NM_001195798.2:c.2125A>G
NM_001195799.2:c.2002A>G
NM_001195800.2:c.1621A>G
NM_001195803.2:c.1606+274A>G

Uncertain Significance

• Met criteria codes: PP4 PM2

• Not Met criteria codes: BP4 PP3 PM5 PS3

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.2125A>G (p.Arg709Gly) variant is classified as Uncertain significance – insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024. The supporting evidence is as follows: PM2: PopMax MAF=0.000004237 in non-Finnish European exomes (gnomAD v4.1.0). PP4: Variant meets PM2, and is identified in one index case with DLCN score >=6 after alternative causes of high cholesterol were excluded, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France.

Met criteria codes

• PP4: Variant meets PM2, and is identified in one index case who fulfils DLCN ≥6 criteria for FH after alternative causes of high cholesterol were excluded. This case is reported in ClinVar and ClinGen VCI from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).
• PM2: PopMaxMAF=0.000004237 in non-Finnish European exomes (gnomAD v4.1.0).

Not Met criteria codes

• BP4: REVEL= 0.746, which is not above impact threshold, splicing evaluation required. MES: A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, however does not create GT. C) there is no GT nearby. Variant is not predicted to alter splicing.
• PP3: REVEL= 0.746, which is not above impact threshold, splicing evaluation required.
• PM5: One other variant in the same codon: NM_000527.5 (LDLR):c2126G>A (p.Arg709Lys)(ClinVarID 183132) is classified as VUS by these guidelines. Therefore, PM5 is not met.
• PS3: Functional data not available.