Variant: NM_000527.5(LDLR):c.845T>G (p.Phe282Cys)

CA404080624

977997 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 8ec9b766-260e-4587-8f2c-cec8efefbe1f

HGVS expressions

NM_000527.5:c.845T>G
NM_000527.5(LDLR):c.845T>G (p.Phe282Cys)
NC_000019.10:g.11107419T>G
CM000681.2:g.11107419T>G
NC_000019.9:g.11218095T>G
CM000681.1:g.11218095T>G
NC_000019.8:g.11079095T>G
NG_009060.1:g.23039T>G
ENST00000558518.6:c.845T>G
ENST00000252444.9:n.1099T>G
ENST00000455727.6:c.341T>G
ENST00000535915.5:c.722T>G
ENST00000545707.5:c.464T>G
ENST00000557933.5:c.845T>G
ENST00000558013.5:c.845T>G
ENST00000558518.5:c.845T>G
ENST00000558528.1:n.360T>G
ENST00000560467.1:n.445T>G
NM_000527.4:c.845T>G
NM_001195798.1:c.845T>G
NM_001195799.1:c.722T>G
NM_001195800.1:c.341T>G
NM_001195803.1:c.464T>G
NM_001195798.2:c.845T>G
NM_001195799.2:c.722T>G
NM_001195800.2:c.341T>G
NM_001195803.2:c.464T>G

Uncertain Significance

• Met criteria codes: PM2 PP3

• Not Met criteria codes: PM6 PM5 PM3 PM1 PM4 PVS1 BS4 BS3 BS1 BS2 BP2 BP3 BP4 BA1 PS1 PS2 PS4 PS3 PP4 PP1

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.845T>G (p.Phe282Cys) 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=0.975. It is above 0.75, so PP3 is met.

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So, PM2 is met.
• PP3: REVEL=0.975. It is above 0.75, so PP3 is met.

Not Met criteria codes

• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 4 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.844T>C (p.Phe282Leu) (ClinVar ID 977996) - classified as uncertain significance by these guidelines - NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) (ClinVar ID 183098) - classified as Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PM3: No data available
• PM1: Not in exon 4. Not a cysteine residue.
• PM4: No in-frame deletions/insertions
• PVS1: Not a null variant.
• BS4: No data available
• BS3: No data available
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BS2: No data available
• BP2: No data available
• BP3: No in-frame deletions/insertions
• BP4: REVEL=0.975. It is above 0.5
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• PS1: No other missense variant in this codon 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
• PS4: No data available
• PS3: No data available
• PP4: No data available
• PP1: No data available

Approved on: 2023-04-28

Published on: 2023-04-30