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.914G>C (p.Trp305Ser)

CA10585190

251519 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

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

PP4 PP1 PS4_Supporting PM2

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

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.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).

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.

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.

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.

PVS1

Not a null variant.

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).

PM6

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

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).

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

BS2

No data available.

BP2

No data available.

BP3

No in-frame deletions/insertions

BP4

REVEL=0.718. It is above 0.5.

Approved on: 2023-04-28

Published on: 2023-04-30

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