8-19954279-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_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:11

Conservation

PhyloP100: 7.52

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

familial lipoprotein lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
hyperlipidemia, familial combined, LPL related
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

LPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000237.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 1527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.701C>T	p.Pro234Leu	missense_variant	Exon 5 of 10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 link	c.701C>T	p.Pro234Leu	missense_variant	Exon 5 of 10		NM_000237.3	ENSP00000497642.1		P06858
LPL	ENST00000520959.5 link	c.*128C>T		downstream_gene_variant		4		ENSP00000428496.1		E7EW14

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

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251454

AF XY:

0.0000368

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000405

AC:

AN:

1112004

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000513

Hom.:

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type I

Pathogenic:3

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 06, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 strong, PM2 moderated, PM3 strong, PP3 supporting -

May 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hyperlipidemia, familial combined, LPL related

Pathogenic:2

Dec 05, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jun 02, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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:2

Oct 23, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PP1_strong, PM1, PM2, PM3, PS3_supp, PP2, PP3, PP5 -

Nov 04, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I

Pathogenic:1

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LPL-related disorder

Pathogenic:1

Feb 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

7.5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over