rs118204068

Positions:

chr8-19955894-G-A

Variant summary

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

The NM_000237.3(LPL):c.829G>A(p.Asp277Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,966 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. D277D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.94

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000237.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 8-19955894-G-A is Pathogenic according to our data. Variant chr8-19955894-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1539.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.829G>A	p.Asp277Asn	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.829G>A	p.Asp277Asn	missense_variant	6/10		NM_000237.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

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:

0.0000159

AC:

AN:

251314

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727234

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:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

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

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type I

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1992	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 15, 2019	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the LPL protein (p.Asp277Asn). This variant is present in population databases (rs118204068, gnomAD 0.005%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 1639392, 25966443, 29748148, 30150141). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Asp250Asn. ClinVar contains an entry for this variant (Variation ID: 1539). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 1639392). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 12, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2020

The p.D277N pathogenic mutation (also known as c.829G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at nucleotide position 829. The aspartic acid at codon 277 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states in numerous individuals with familial chylomicronemia syndrome (FCS) (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Wiebusch H et al. Hum. Mutat., 1996;8:381-3; Bijvoet SM et al. Neth J Med, 1996 Nov;49:189-95; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8; Ma Y et al. Genomics, 1992 Jul;13:649-53; Rodrigues R et al. J Clin Lipidol Dec;10:394-409; Ariza MJ et al. J Clin Lipidol Aug;12:1482-1492.e3; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). In the heterozygous state, this variant has been associated with moderate to severe hypertriglyceridemia (Surendran RP et al. J. Intern. Med., 2012 Aug;272:185-96; Minicocci I et al. Atherosclerosis, 2015 Oct;242:618-24). Functional studies indicate that this alteration results in deficient protein function (Ishimura-Oka K et al. J. Lipid Res., 1992 May;33:745-54; Ma Y et al. Genomics, 1992 Jul;13:649-53; Martín-Campos JM et al. Clin. Chim. Acta, 2014 Feb;429:61-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.045

D;.

Polyphen

0.66

P;P

Vest4

0.94

MutPred

0.92

Loss of stability (P = 0.1586);Loss of stability (P = 0.1586);

MVP

0.99

MPC

0.20

ClinPred

0.95

GERP RS

6.1

Varity_R

0.85

gMVP

0.90

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