NM_000237.3:c.1385T>C

LPL · NP_000228.1:p.(Phe462Ser) · NM_000237.3

GRCh37: chr8:19819688 T>C · GRCh38: chr8:19962177 T>C

Gene: LPL Transcript: NM_000237.3

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

LPL

Transcript

NM_000237.3

Protein

NP_000228.1:p.(Phe462Ser)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_variant_assessment spliceai
PS1	Not assessed	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.
PS2	Not assessed	No confirmed de novo occurrence was identified. Available evidence does not document maternity and paternity confirmation in an affected individual.
PS3	Not assessed	No well-established functional study of this exact variant was identified showing a damaging effect on lipoprotein lipase function, so PS3 is not applied.
PS4	Not assessed	The available data do not show a statistically increased prevalence of this variant in affected individuals compared with controls, so PS4 cannot be applied.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	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.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	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.
PM4	N/A	This variant is a missense substitution and does not produce a protein length change, so PM4 is not applicable.
PM5	Not assessed	No evidence was identified for a different pathogenic missense change at codon 462, so PM5 cannot be applied from the available data.
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified, so PM6 is not applied.
PP1	Not assessed	No segregation data were identified showing that this variant tracks with LPL-related disease in a family, so PP1 cannot be applied.
PP2	Not assessed	Available evidence does not establish a gene-specific pattern that would support applying PP2 to this missense variant.
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	No case-specific phenotype information was provided that is sufficiently specific for an LPL-related disorder, so PP4 cannot be assessed.
PP5	N/A	A 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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	Available population data do not show well-established benign observations in healthy adults that would support BS2 for this variant.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing normal or near-normal function for this exact variant, so BS3 is not applied.
BS4	Not assessed	No non-segregation data were identified showing that this variant fails to track with disease in a family, so BS4 cannot be applied.
BP1	Not assessed	Available evidence does not establish a gene-specific pattern to support BP1 for this missense variant.
BP2	Not assessed	No phase information or accompanying variant data were identified to assess BP2.
BP3	N/A	This variant is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular explanation was identified that would make this variant an incidental finding, so BP5 cannot be assessed from the available data.
BP6	N/A	A 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.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 is not applicable.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.