rs118204057

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_000237.3(LPL):c.644G>A(p.Gly215Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G215R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.48

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 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000237.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 8-19954222-G-A is Pathogenic according to our data. Variant chr8-19954222-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19954222-G-A is described in Lovd as [Pathogenic]. Variant chr8-19954222-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.644G>A	p.Gly215Glu	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.644G>A	p.Gly215Glu	missense_variant	5/10		NM_000237.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000655

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:

0.000294

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251454

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000367

AC:

537

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

273

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000444

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000243

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000269

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2022	Reported in the heterozygous state in association with hyperlipoproteinemia or hypertriglyceridemia (Chokshi et al., 2014; Johansen et al., 2014; Rodrigues et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 1522; ClinVar); Functional studies have demonstrated that G215E results in a complete loss of catalytic activity (Hata et al., 1992); This variant is associated with the following publications: (PMID: 28534127, 1619366, 1969408, 12905705, 18922999, 24793350, 24503134, 27055971, 24747307, 22095987, 24493316, 1975597, 1400331, 30150141, 29748148, 30210108, 32472350, 28438574, 29288010, 34426522, 31589614, 32041611, 33303402, 1351946) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 14, 2023	PP1_strong, PM3, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 215 of the LPL protein (p.Gly215Glu). This variant is present in population databases (rs118204057, gnomAD 0.03%). This missense change has been observed in individuals with lipoprotein lipase deficiency (PMID: 1969408, 22095987, 28438574). This variant is also known as p.Gly188Glu. ClinVar contains an entry for this variant (Variation ID: 1522). 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 not expected to disrupt LPL protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 1400331, 1969408, 29288010). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hyperlipidemia, familial combined, LPL related

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 29, 2019	The c.644G>A (p.Gly215Glu) variant (also known as Gly188Glu, rs118204057) in the LPL gene has been reported numerous times in association with autosomal recessive LPL deficiency when present in the homozygous or compound heterozygous state (PMID: 1975597, 29288010, 29748148). It has also been reported in association with significantly elevated triglyceride levels and pancreatitis in the heterozygous state (PMID: 24793350, 2719595, 22239554). This variant is present in 50/282856 alleles in the gnomAD population database. Functional studies show a loss of enzyme activity resulting from this variant (PMID: 1400331). This variant is considered pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Aug 05, 2024	The p.Gly215Glu variant in LPL has been reported in >10 individuals with familial combined hyperlipidemia (PMID: 1975597, 1969408, 11334614, 30352774, 36274861, 36476373, 35460704, 22095987), but has been identified in 0.2% (2/912) of Amish chromosomes and other populations at a lesser frequency by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204057). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at frequency higher than expected in the general population. In vitro functional studies provide some evidence that the p.Gly215Glu variant may slightly impact protein function (PMID: 1969408, 29288010). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant familial combined hyperlipidemia. ACMG/AMP Criteria applied: PS4_strong, PP3, PS3_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 17, 2022	The c.644G>A p.(Gly215Glu) variant [historically called p.(Gly188Glu) in the literature] has previously been reported in multiple individuals in homozygous or compound heterozygous state with lipoprotein lipase deficiency [PMID: 1975597, 29288010, 29748148, 30210108, 27055971, 1969408, 1351946]. Moreover, the variant co-segregated with the disease in multiple affected family members [PMID:26337181, 1969408]. In the heterozygous sate, this variant has been reported in individuals with elevated triglyceride levels [PMID: 24793350, 2719595, 22239554, 27055971]. The variant has been deposited in ClinVar [ClinVar ID: 1522] as LikelyPathogenic/Pathogenic (6 entries) and Variant of Uncertain Significance (1 entry). The c.644G>A variant is observed in 85 alleles (0.00021 minor allele frequency with0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2). The c.644G>A variant is located in exon 5 of this 10-exon gene and is predicted to replace an evolutionarily conserved glycine amino acid with glutamic acid at codon 215 in the lipase domain of the encoded protein [PMID: 34544385]. In silico predictions are in favor of the damaging effect for the p.(Gly215Glu) variant [REVEL score =0.705]. In vitro functional studies demonstrated reduced catalytic activity and protein function in HEK293T and COS-1 cells carrying c.644G>A variant [PMID: 1400331, 29288010, 1969408]. Based on available evidence this c.644G>A p.(Gly215Glu) variant identified in LPL is classified as Pathogenic. -

Hyperlipoproteinemia, type I

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.644G>A;p.(Gly215Glu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1522; PMID: 29288010; 22095987; 9401010; 1351946; PMID: 26337181) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 29288010) - PS3_supporting. The variant is present at low allele frequencies population databases (rs118204057– gnomAD 0.002432%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly215Glu) was detected in trans with a pathogenic variant (PMID: 29288010; 22095987; 9401010; 1351946; 26337181) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 26337181) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 29288010) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The p.G215E pathogenic mutation (also known as c.644G>A), located in coding exon 5 of the LPL gene, results from a G to A substitution at nucleotide position 644. The glycine at codon 215 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been reported to be a founder mutation and has been detected in the homozygous and compound heterozygous states in numerous individuals with familial chylomicronemia (FCS) (e.g., Monsalve MV et al. J. Clin. Invest., 1990 Sep;86:728-34; Henderson HE et al. J. Med. Genet., 1992 Feb;29:119-22; Gilbert B et al. Ann. Genet.2011;44:25-32; Hooper AJ et al. Ann. Clin. Biochem., 2014 Jul;51:485-9; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86; Hegele RA et al. J Clin Lipidol 2018 Apr;12:920-927.e4). In the heterozygous state, this alteration has been associated with hyperlipoproteinemia (Chokshi N et al. J Clin Lipidol 2014 Feb;8:287-95; Johansen CT et al. J. Lipid Res., 2014 Apr;55:765-72; Rodrigues R et al. J Clin Lipidol 2016 Dec;10:394-409). Functional studies indicate that this alteration results in deficient protein function (Emi M et al. J. Biol. Chem., 1990 Apr;265:5910-6; Hata A et al. J. Biol. Chem., 1992 Oct;267:20132-9; Caddeo A et al. Nutr Metab Cardiovasc Dis, 2018 02;28:158-164). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

LPL-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The LPL c.644G>A variant is predicted to result in the amino acid substitution p.Gly215Glu. This variant (also known as p.Gly188Glu), has been reported in the homozygous or compound heterozygous state in multiple patients with lipoprotein lipase deficiency and familial chylomicronemia syndrome (FCS) (Emi et al. 1990. PubMed ID: 1969408; Monsalve et al. 1990. PubMed ID: 1975597; Ooi et al. 2012. PubMed ID: 22095987; Bordugo et al. 2014. PubMed ID: 24747307; Hegele et al. 2018. PubMed ID: 29748148; Ariza et al. 2018. PubMed ID: 30150141). Heterozygous carriers of this variant are also reported to have a wide range of fasting triglyceride concentrations (Wilson et al. 1990. PubMed ID: 2394828; Hooper et al. 2008. PubMed ID: 18275685; Chokshi et al. 2014. PubMed ID: 24793350; Johansen et al. 2014. PubMed ID: 24503134; Rodrigues et al. 2016. PubMed ID: 27055971). Functional studies also suggest this variant decreases LPL protein activity (Caddeo et al. 2018. PubMed ID: 29288010). This variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.35

T;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.1

N;.

REVEL

Pathogenic

0.70

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Polyphen

1.0

D;D

Vest4

0.96

MVP

1.0

MPC

0.50

ClinPred

0.15

GERP RS

5.3

Varity_R

0.44

gMVP

0.92

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