rs118204060

Positions:

chr8-19954279-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000237.3(LPL):c.701C>T(p.Pro234Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P234P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

LPL (HGNC:6677): (lipoprotein lipase) LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

LPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000237.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 8-19954279-C-T is Pathogenic according to our data. Variant chr8-19954279-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.701C>T	p.Pro234Leu	missense_variant	5/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.701C>T	p.Pro234Leu	missense_variant	5/10		NM_000237.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251454

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type I

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.701C>T;p.(Pro234Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1527; OMIM: 609708.0009; PMID: 8099055; 1511985; 2038366) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 8099055) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Lipase) - PM1. The variant is present at low allele frequencies population databases (rs118204060– gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Pro234Leu) was detected in trans with a pathogenic variant (PMID: 8099055) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 8099055; 1511985) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 06, 2022	ACMG classification criteria: PS4 strong, PM2 moderated, PM3 strong, PP3 supporting -

Hyperlipidemia, familial combined, LPL related

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 05, 2018	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2022	Reported as the most prevalent founder mutation in the French Canadaian population (Normand et al., 1992; Wood et al., 1993; Bijvoet et al., 1996); Published functional studies suggest impaired LPL activity in transfected cells (Ma et al., 1991).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 30150141, 32041611, 2038366, 24366202, 29748148, 8099055, 8728325, 27055971, 17560523, 1511985) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 12, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 234 of the LPL protein (p.Pro234Leu). This variant is present in population databases (rs118204060, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 2038366, 24366202, 29748148, 30150141). ClinVar contains an entry for this variant (Variation ID: 1527). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LPL protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2019

The p.P234L pathogenic mutation (also known as c.701C>T), located in coding exon 5 of the LPL gene, results from a C to T substitution at nucleotide position 701. The proline at codon 234 is replaced by leucine, an amino acid with similar properties. This variant (also referred to as P207L) has been reported as a French Canadian founder mutation and has been detected in the homozygous and compound heterozygous state in numerous individuals with familial chylomicronemia syndrome with reduced lipoprotein lipase enzyme activity (Ma Y et al. N. Engl. J. Med., 1991 Jun;324:1761-6; Yang Y et al. J Genet Genomics, 2007 May;34:381-91; Sacks FM et al. JAMA Intern Med, 2014 Mar;174:443-7; Ariza MJ et al. J Clin Lipidol 2018 Aug;12:1482-1492.e3; Hegele RA et al. J Clin Lipidol 2018 Apr;12:920-927.e4; Normand T et al. Hum. Genet., 1992 Aug;89:671-5). This variant has also been detected in the heterozygous state in individuals with hypertriglyceridemia (Yang Y et al. J Genet Genomics, 2007 May;34:381-91). This mutation has been reported to result in a catalytically defective protein with abnormal conformation (Ma Y et al. N. Engl. J. Med., 1991 Jun;324:1761-6; Peterson J et al. J. Lipid Res., 2002 Mar;43:398-406). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

LPL-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

The LPL c.701C>T variant is predicted to result in the amino acid substitution p.Pro234Leu. This variant has been reported in the homozygous or compound heterozygous state in multiple patients with lipoprotein lipase deficiency and familial chylomicronemia syndrome (FCS) (Hegele et al. 2018. PubMed ID: 29748148; Ariza et al. 2018. PubMed ID: 30150141; Rodrigues et al. 2016. PubMed ID: 27055971). This variant is also a common cause of lipoprotein lipase deficiency among French Canadians, and functional data indicate the p.Pro234Leu substitution reduces LPL protein activity significantly (Ma et al. 1991. PubMed ID: 2038366). In summary, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-9.8

D;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.96

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.97

MPC

0.45

ClinPred

0.99

GERP RS

6.2

Varity_R

0.97

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over