8-19955873-C-T

Position:

chr8-19955873-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.10

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 16 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, 3 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 [Likely_pathogenic]. Clinvar id is 1530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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]. Clinvar id is 1548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19955873-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.808C>T	p.Arg270Cys	missense_variant	6/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.808C>T	p.Arg270Cys	missense_variant	6/10		NM_000237.3	P1

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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251278

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135800

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:

0.0000653

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: 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	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 1548). This variant is also known as p.Arg243Cys. This missense change has been observed in individuals with clinical features of lipoprotein lipase deficiency (PMID: 7906986, 25966443, 29153744). This variant is present in population databases (rs118204077, gnomAD 0.006%). 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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2021

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. -

LPL-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

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

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

MutationTaster

Benign

1.0

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

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