Classification rationale

PM2PP3 VUS

LPL c.1385T>C

The LPL c.1385T>C (p.Phe462Ser; p.F462S) variant has been reported in ClinVar as uncertain significance by two clinical laboratories.¹ This variant is rare in population databases, with allele frequencies of 0.00080% in gnomAD v2.1 (2/251272) and 0.00037% in gnomAD v4.1 (6/1613776), which are both below the 0.1% PM2 threshold.² Computational evidence supports a deleterious effect, with REVEL 0.735 and BayesDel 0.304545, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.³

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_000237.3 · variants mapped to exon structure

LPL NM_000237.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.71799e-06; MAF= 0.00037%, 6/1613776 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66683e-05; MAF= 0.00167%, 1/59994 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.9595e-06; MAF= 0.00080%, 2/251272 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43656e-05; MAF= 0.00544%, 1/18394 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00037% · 6 / 1,613,776
0 hom · FAF 7.9e-05%

Admixed American 1 / 59,994	0.0017%
South Asian 1 / 91,082	0.0011%
European (non-Finnish) 4 / 1,179,830	0.00034%

+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0008% · 2 / 251,272
0 hom

East Asian 1 / 18,394	0.0054%
South Asian 1 / 30,614	0.0033%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.735. BayesDel score = 0.304545.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots