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LPLc.1385T>CUncertain significance
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Variant interpretation report

LPL c.1385T>C, p.(Phe462Ser)

NM_000237.3:c.1385T>C NP_000228.1:p.(Phe462Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About LPL

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Moderate
PM2 · moderate

This variant is rare in population databases. In gnomAD v2.1 the allele frequency is 0.00080% (2/251272), and in gnomAD v4.1 the allele frequency is 0.00037% (6/1613776), both below the 0.1% PM2 threshold.

PP3Supporting
PP3 · supporting

Multiple computational predictors support a deleterious effect. REVEL is 0.735 and BayesDel is 0.304545, both consistent with a damaging missense effect, while SpliceAI shows no significant splice impact with a max delta score of 0.04. Overall, the in silico evidence supports pathogenicity at a supporting level.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, PP3 supporting; combination = 1 moderate + 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,613,776 alleles

gnomAD v4.1: 6 / 1,613,776 alleles. Recorded AF 3.71799e-06. Recorded homozygote count 0.

gnomAD 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).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The LPL c.1385T>C (p.Phe462Ser; p.F462S) variant has been reported in ClinVar as uncertain significance by two clinical laboratories.

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.

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.

Met · 2

PM2 ModerateThis variant is rare in population databases. In gnomAD v2.1 the allele frequency is 0.00080% (2/251272), and in gnomAD v4.1 the allele frequency is 0.00037% (6/1613776), both below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 7.9595e-06 (2/251272)
  • gnomAD v4.1 AF 3.71799e-06 (6/1613776)
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingMultiple computational predictors support a deleterious effect. REVEL is 0.735 and BayesDel is 0.304545, both consistent with a damaging missense effect, while SpliceAI shows no significant splice impact with a max delta score of 0.04. Overall, the in silico evidence supports pathogenicity at a supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL 0.735
  • BayesDel 0.304545
  • SpliceAI max delta score 0.04
Sources
revelbayesdelspliceai ↗

Not met · 4 · evaluated, threshold not reached

PM1 This variant has not been shown to lie in a statistically significant hotspot or other well-established critical functional region without benign variation, so PM1 is not met. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review found no hotspot row for residue F462
Still missing
  • A curated critical-region or pathogenic clustering dataset for this residue was not identified.
Sources
hotspots ↗
BA1 This variant is not common enough for BA1. The highest observed population frequency is 0.00544% in gnomAD v2.1 East Asian and 0.00167% in gnomAD v4.1 Admixed American, both below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Highest gnomAD v2.1 subpopulation AF 0.00544%
  • Highest gnomAD v4.1 subpopulation AF 0.00167%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant does not reach the BS1 threshold. The highest observed population frequency is 0.00544% in gnomAD v2.1 and 0.00167% in gnomAD v4.1, both below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Highest gnomAD v2.1 subpopulation AF 0.00544%
  • Highest gnomAD v4.1 subpopulation AF 0.00167%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Available computational evidence does not support a benign effect. REVEL is 0.735 and BayesDel is 0.304545, which do not favor benignity, although SpliceAI shows no significant splice impact with a max delta score of 0.04. Details ▾Hide ▴
Evidence considered
  • REVEL 0.735
  • BayesDel 0.304545
  • SpliceAI max delta score 0.04
Sources
revelbayesdelspliceai ↗

Not assessed · 16 · no assessment recorded

PS1 No evidence was identified that another nucleotide change produces the same amino acid substitution with an established pathogenic classification, so PS1 cannot be applied from the available data. Details ▾Hide ▴
Still missing
  • Evidence for a different pathogenic nucleotide change causing the same amino acid substitution was not identified.
PS2 No confirmed de novo occurrence was identified. Available evidence does not document maternity and paternity confirmation in an affected individual. Details ▾Hide ▴
Still missing
  • Trio-confirmed de novo case data were not identified.
PS3 No well-established functional study of this exact variant was identified showing a damaging effect on lipoprotein lipase function, so PS3 is not applied. Details ▾Hide ▴
Still missing
  • Variant-specific functional assay data were not identified.
PS4 The available data do not show a statistically increased prevalence of this variant in affected individuals compared with controls, so PS4 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ClinVar reports uncertain significance submissions only
  • gnomAD shows rare population presence
Still missing
  • Affected-case counts and enrichment data for this exact variant were not identified.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in an affected individual, so PM3 cannot be assessed from the available data. Details ▾Hide ▴
Still missing
  • Phase and partner-variant data were not identified.
PM5 No evidence was identified for a different pathogenic missense change at codon 462, so PM5 cannot be applied from the available data. Details ▾Hide ▴
Still missing
  • Pathogenic missense variation at the same codon was not identified.
PM6 No assumed de novo occurrence without confirmed parentage was identified, so PM6 is not applied. Details ▾Hide ▴
Still missing
  • A de novo case report without full parentage confirmation was not identified.
PP1 No segregation data were identified showing that this variant tracks with LPL-related disease in a family, so PP1 cannot be applied. Details ▾Hide ▴
Still missing
  • Family segregation data were not identified.
PP2 Available evidence does not establish a gene-specific pattern that would support applying PP2 to this missense variant. Details ▾Hide ▴
Still missing
  • A validated gene-level missense constraint rule for PP2 was not identified.
PP4 No case-specific phenotype information was provided that is sufficiently specific for an LPL-related disorder, so PP4 cannot be assessed. Details ▾Hide ▴
Still missing
  • Phenotypic data for the tested individual were not identified.
BS2 Available population data do not show well-established benign observations in healthy adults that would support BS2 for this variant. Details ▾Hide ▴
Evidence considered
  • No homozygotes observed in gnomAD v2.1 or v4.1
Still missing
  • Validated healthy-adult observations appropriate for BS2 were not identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study was identified showing normal or near-normal function for this exact variant, so BS3 is not applied. Details ▾Hide ▴
Still missing
  • Variant-specific benign functional assay data were not identified.
BS4 No non-segregation data were identified showing that this variant fails to track with disease in a family, so BS4 cannot be applied. Details ▾Hide ▴
Still missing
  • Family non-segregation data were not identified.
BP1 Available evidence does not establish a gene-specific pattern to support BP1 for this missense variant. Details ▾Hide ▴
Still missing
  • A validated gene-level rule favoring truncating over missense pathogenicity was not identified.
BP2 No phase information or accompanying variant data were identified to assess BP2. Details ▾Hide ▴
Still missing
  • Phase and second-variant data were not identified.
BP5 No alternate molecular explanation was identified that would make this variant an incidental finding, so BP5 cannot be assessed from the available data. Details ▾Hide ▴
Still missing
  • An alternate established cause for the phenotype was not identified.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Phe462Ser) / p.(F462S), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Available splice prediction also does not suggest a loss-of-function transcript effect. Details ▾Hide ▴
Evidence considered
  • Missense change NM_000237.3:c.1385T>C
  • NP_000228.1:p.(Phe462Ser) / p.(F462S)
  • Generic PVS1 framework not triggered
  • SpliceAI max delta score 0.04
Sources
pvs1_variant_assessmentspliceai ↗
PM4 N/AThis variant is a missense substitution and does not produce a protein length change, so PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PP5 N/AA prior laboratory classification in ClinVar is not used as stand-alone evidence for PP5. The available ClinVar record is uncertain significance and does not provide independent evidence to apply this criterion. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: uncertain significance
Sources
clinvar ↗
BP3 N/AThis variant is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP6 N/AA prior laboratory classification in ClinVar is not used as stand-alone evidence for BP6. The available ClinVar record is uncertain significance and does not provide independent evidence to apply this criterion. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: uncertain significance
Sources
clinvar ↗
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
LPL
Transcript
NM_000237.3
Coding (HGVS c.)
NM_000237.3:c.1385T>C
Protein (HGVS p.)
NP_000228.1:p.(Phe462Ser)
GRCh38
chr8:19962177 T>C
GRCh37
chr8:19819688 T>C

Gene diagram

Every interpreted variant in LPL, mapped onto the exon structure of NM_000237.3. Select a row to find it on the plot.

LPLNM_000237.3
Fetching transcript structure from UCSC…
gnomAD v4.1 6 / 1,613,776 alleles AF 3.72e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1 2 / 251,272 alleles AF 7.96e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 3.7e-06 · 6 / 1,613,776 alleles · 0 hom · FAF 7.9e-07
Admixed American1 / 59,994 1.7e-05
South Asian1 / 91,082 1.1e-05
European (non-Finnish)4 / 1,179,830 3.4e-06
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8e-06 · 2 / 251,272 alleles · 0 hom
East Asian1 / 18,394 5.4e-05
South Asian1 / 30,614 3.3e-05
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.

Statements

gnomAD 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.

gnomAD 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).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SupportingMultiple computational predictors support a deleterious effect. REVEL is 0.735 and BayesDel is 0.304545, both consistent with a damaging missense effect, while SpliceAI shows no significant splice impact with a max delta score of 0.04. Overall, the in silico evidence supports pathogenicity at a supporting level. Details ▾Hide ▴
Evidence considered
  • REVEL 0.735
  • BayesDel 0.304545
  • SpliceAI max delta score 0.04
Sources
revelbayesdelspliceai ↗
BP4 Available computational evidence does not support a benign effect. REVEL is 0.735 and BayesDel is 0.304545, which do not favor benignity, although SpliceAI shows no significant splice impact with a max delta score of 0.04. Details ▾Hide ▴
Evidence considered
  • REVEL 0.735
  • BayesDel 0.304545
  • SpliceAI max delta score 0.04
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 6 / 1,613,776 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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).

ClinVar

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

In silico

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

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.