Variant: NM_000527.5(LDLR):c.1738T>C (p.Ser580Pro)

CA16602336

375822 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: dbe69dff-fc05-4b5e-bb6a-5c4520cdc0a0

Approved on: 2023-11-07

Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1738T>C
NM_000527.5(LDLR):c.1738T>C (p.Ser580Pro)
NC_000019.10:g.11116891T>C
CM000681.2:g.11116891T>C
NC_000019.9:g.11227567T>C
CM000681.1:g.11227567T>C
NC_000019.8:g.11088567T>C
NG_009060.1:g.32511T>C
ENST00000252444.10:c.1996T>C
ENST00000559340.2:c.1705+679T>C
ENST00000560467.2:c.1618T>C
ENST00000558518.6:c.1738T>C
ENST00000252444.9:c.1992T>C
ENST00000455727.6:c.1234T>C
ENST00000535915.5:c.1615T>C
ENST00000545707.5:c.1357T>C
ENST00000557933.5:c.1738T>C
ENST00000558013.5:c.1738T>C
ENST00000558518.5:c.1738T>C
ENST00000559340.1:c.426+679T>C
NM_000527.4:c.1738T>C
NM_001195798.1:c.1738T>C
NM_001195799.1:c.1615T>C
NM_001195800.1:c.1234T>C
NM_001195803.1:c.1357T>C
NM_001195798.2:c.1738T>C
NM_001195799.2:c.1615T>C
NM_001195800.2:c.1234T>C
NM_001195803.2:c.1357T>C

Uncertain Significance

• Met criteria codes: PM2 PP4 PP3

• Not Met criteria codes: BA1 PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP2 BP3 BP4 PVS1 PS2 PS3 PS1 PS4 PP1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1738T>C (p.Ser580Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.911. PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria 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, after alternative causes of high cholesterol were excluded.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.
• PP4: Variant meets PM2. Identified in 1 FH case fromCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) with Simon Broome criteria of possible FH, after alternative causes of high cholesterol were excluded. So, PP4 is met.
• PP3: REVEL=0.911. It is above 0.75, so PP3 is met.

Not Met criteria codes

• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• PM3: No data available
• PM1: Not in exon 4. Not a cysteine residue.
• PM4: No in-frame deletions/insertions
• PM5: 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) (ClinVar ID 438325) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1739C>G (p.Ser580Cys) (ClinVar ID 921461) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No data available.
• BS4: No data available
• BS3: No data available
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BP2: No data available
• BP3: No in-frame deletions/insertions
• BP4: REVEL=0.911. It is above 0.5
• PVS1: Not a null variant
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No data available
• PS1: No other missense variants with the same amino acid change.
• PS4: Variant meets PM2. Identified in 1 FH case fromCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) with Simon Broome criteria of possible FH, after alternative causes of high cholesterol were excluded.
• PP1: No data available