Variant: NM_000527.5(LDLR):c.914G>C (p.Trp305Ser)

CA10585190

251519 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 9eab8981-0be2-4163-97fc-231bb81ed509

Approved on: 2023-04-28

Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.914G>C
NM_000527.5(LDLR):c.914G>C (p.Trp305Ser)
NC_000019.10:g.11107488G>C
CM000681.2:g.11107488G>C
NC_000019.9:g.11218164G>C
CM000681.1:g.11218164G>C
NC_000019.8:g.11079164G>C
NG_009060.1:g.23108G>C
ENST00000558518.6:c.914G>C
ENST00000252444.9:n.1168G>C
ENST00000455727.6:c.410G>C
ENST00000535915.5:c.791G>C
ENST00000545707.5:c.533G>C
ENST00000557933.5:c.914G>C
ENST00000558013.5:c.914G>C
ENST00000558518.5:c.914G>C
ENST00000558528.1:n.429G>C
ENST00000560467.1:n.514G>C
NM_000527.4:c.914G>C
NM_001195798.1:c.914G>C
NM_001195799.1:c.791G>C
NM_001195800.1:c.410G>C
NM_001195803.1:c.533G>C
NM_001195798.2:c.914G>C
NM_001195799.2:c.791G>C
NM_001195800.2:c.410G>C
NM_001195803.2:c.533G>C

Uncertain Significance

• Met criteria codes: PM2 PS4_Supporting PP4 PP1

• Not Met criteria codes: PM5 PM3 PM1 PM4 PM6 PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 PS1 PS2 PS3 PP3 BA1

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.914G>C (p.Trp305Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS4_Supporting, 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_Supporting: Variant meets PM2 and is identified in 2 index cases with DLCN criteria of probable FH from Lille University & CHRU Lille. So, PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from 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 in 2 index cases who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded (see PS4 for details).

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.
• PS4_Supporting: Variant meets PM2 and is identified in 2 index cases with DLCN criteria of probable FH from Lille University & CHRU Lille. So, PS4_Supporting is met.
• PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded (see PS4 for details).
• PP1: Variant segregates with FH phenotype in 2 informative meioses in 1 families from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So, PP1 is met.

Not Met criteria codes

• PM5: 2 other missense variants in the same codon: NM_000527.5(LDLR):c.915G>T (p.Trp305Cys) (ClinVar ID 1437514) Uncertain significance by these guidelines NM_000527.5(LDLR):c.915G>C (p.Trp305Cys) (ClinVar ID 251521) Uncertain significance by these guidelines No other pathogenic missense variants in the same codon.
• PM3: No data available.
• PM1: Not on exon 4. Not a cysteine residue.
• PM4: No in-frame deletions/insertions
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: Not a null variant.
• BS2: No data available.
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No functional studies available.
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BP2: No data available.
• BP3: No in-frame deletions/insertions
• BP4: REVEL=0.718. It is above 0.5.
• PS1: No other missense variant with the same amino acid change
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No functional studies available.
• PP3: REVEL=0.718. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site, but it does not create GT. C) there is a GT nearby. MES scores: variant cryptic = -2.53, wt cryptic = 3.96, canonical donor = 10.49. Ratio variant cryptic/wt cryptic: -2.53/3.96 = -0.63 --- it is not above 1.1 Ratio variant cryptic/canonical donor: -2.53/10.49 = -0.24--- it is not above 0.9 Variant is not predicted to alter splicing.
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).