8-19955873-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000237.3(LPL):c.808C>T(p.Arg270Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. 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. R270H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.10

Publications

13 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 17 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000237.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-19955874-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.995

PP5

Variant 8-19955873-C-T is Pathogenic according to our data. Variant chr8-19955873-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1548.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.808C>T	p.Arg270Cys	missense_variant	Exon 6 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 link	c.808C>T	p.Arg270Cys	missense_variant	Exon 6 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1 link	n.-132C>T		upstream_gene_variant				ENSP00000497560.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251278

AF XY:

0.0000147

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:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000688

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:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type I

Pathogenic:4

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.808C>T;p.(Arg270Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1548; PMID: 29153744; 29748148; 9279761; 7906986) - PS4.The variant is present at low allele frequencies population databases (rs118204077– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg270Cys) was detected in trans with a pathogenic variant (PMID: 29153744; 29748148; 7906986) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID: 1530; PMID: 29748148) - PM5. 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. -

Jan 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LPL c.808C>T (p.Arg270Cys) variant has been reported in individuals affected with lipoprotein lipase deficiency (Rabacchi et al). This variant disrupts the p.Arg270 amino acid residue in LPL. Other variant(s) that disrupt this residue have been observed in individuals with LPL-related conditions (Gotoda et al., 1991), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been reported to the ClinVar database as Pathogenic. The p.Arg270Cys variant is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 270 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg270Cys in LPL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 09, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 270 of the LPL protein (p.Arg270Cys). This variant is present in population databases (rs118204077, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of lipoprotein lipase deficiency (PMID: 7906986, 25966443, 29153744). This variant is also known as p.Arg243Cys. ClinVar contains an entry for this variant (Variation ID: 1548). 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%. This variant disrupts the p.Arg270 amino acid residue in LPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1752947, 7906986, 25966443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:2

Mar 25, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R270C pathogenic mutation (also known as c.808C>T and p.R243C), located in coding exon 6 of the LPL gene, results from a C to T substitution at nucleotide position 808. The arginine at codon 270 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in subjects with features of lipoprotein lipase deficiency (LPL) and has been shown to have an impact on protein function (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64; Rodrigues R et al. J Clin Lipidol Dec;10:394-409; Vidanapathirana DM et al. Glob Pediatr Health, 2017 Jun;4:2333794X17715839; Teramoto R et al. Atherosclerosis, 2018 02;269:272-278; Tada H et al. Clin Chim Acta, 2019 Jan;488:31-39). Other alterations affecting the same amino acid, p.R270H and p.R270G, have also been reported in association with LPL deficiency (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64; Khovidhunkit W et al. J Clin Lipidol Nov;10:505-511.e1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jul 19, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LPL-related disorder

Pathogenic:1

Dec 26, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LPL c.808C>T variant is predicted to result in the amino acid substitution p.Arg270Cys. This variant (aka Arg243Cys) has been previously reported in the heterozygous state, along with second plausible causative variants in the same gene, in two individuals who presented with suspected familial chylomicronemia (Ma et al. 1994. PubMed ID: 7906986). In vitro function studies indicated that the p.Arg270Cys variant resulted in catalytically defective LPL (Ma et al. 1994. PubMed ID: 7906986). This variant was also described in the compound heterozygous or homozygous states state in individuals who presented with familial chylomicronemia (Benlian et al. 1996. PubMed ID: 8778602; Teramoto et al. 2018. PubMed ID: 29153744). Different amino acid changes at this position (p.Arg270Gly, p.Arg270His, and p.Arg270Leu) have also been reported in patients with disease (D’Erasmo et al. 2019. PubMed ID: 31619059, supplementary table 1; Rodrigues et al. 2016. PubMed ID: 27055971). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

PhyloP100

6.1

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.4

D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.99

Gain of helix (P = 0.062);Gain of helix (P = 0.062);

MVP

0.99

MPC

0.51

ClinPred

1.0

GERP RS

6.1

Varity_R

0.94

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over