Variant: NM_000527.5(LDLR):c.844T>C (p.Phe282Leu)

CA404080610

977996 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: e8a0ead8-7572-40fe-bdaa-ff7e2af9ad91

HGVS expressions

NM_000527.5:c.844T>C
NM_000527.5(LDLR):c.844T>C (p.Phe282Leu)
NC_000019.10:g.11107418T>C
CM000681.2:g.11107418T>C
NC_000019.9:g.11218094T>C
CM000681.1:g.11218094T>C
NC_000019.8:g.11079094T>C
NG_009060.1:g.23038T>C
ENST00000558518.6:c.844T>C
ENST00000252444.9:n.1098T>C
ENST00000455727.6:c.340T>C
ENST00000535915.5:c.721T>C
ENST00000545707.5:c.463T>C
ENST00000557933.5:c.844T>C
ENST00000558013.5:c.844T>C
ENST00000558518.5:c.844T>C
ENST00000558528.1:n.359T>C
ENST00000560467.1:n.444T>C
NM_000527.4:c.844T>C
NM_001195798.1:c.844T>C
NM_001195799.1:c.721T>C
NM_001195800.1:c.340T>C
NM_001195803.1:c.463T>C
NM_001195798.2:c.844T>C
NM_001195799.2:c.721T>C
NM_001195800.2:c.340T>C
NM_001195803.2:c.463T>C

Uncertain Significance

• Met criteria codes: PP3 PM2

• Not Met criteria codes: BS2 BS4 BS3 BS1 PVS1 BP3 BP4 PS1 PS2 PS4 PS3 BA1 PP4 PP1 PM6 PM5 PM1 PM4

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.844T>C (p.Phe282Leu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 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: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.985. It is above 0.75, so PP3 is met.

Met criteria codes

• PP3: REVEL=0.985. It is above 0.75, so PP3 is met.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.

Not Met criteria codes

• BS2: No data available.
• BS4: No data available
• BS3: No data available.
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• PVS1: Not a null variant.
• BP3: No in-frame deletions/insertions.
• BP4: REVEL=0.985. It is above 0.5
• PS1: PS1: One more missense variant that leads to the same amino acid change: - NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) (ClinVar ID 183098) - classified as Likely pathogenic by these guidelines
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No data available
• PS3: No data available.
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• PP4: No data available
• PP1: No data available
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.845T>A (p.Phe282Tyr) (ClinVar ID 1763461) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.845T>C (p.Phe282Ser) (ClinVar ID 1466547) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.845T>G (p.Phe282Cys) (ClinVar ID 977997) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PM1: Not in exon 4. Not a cysteine residue.
• PM4: No in-frame deletions/insertions.

Approved on: 2023-04-28

Published on: 2023-04-30