rs118204069

Positions:

chr8-19951856-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000237.3(LPL):c.337T>C(p.Trp113Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,050 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. W113G) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.88

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.

PM5

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 8-19951856-T-C is Pathogenic according to our data. Variant chr8-19951856-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19951856-T-C 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.337T>C	p.Trp113Arg	missense_variant	3/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.337T>C	p.Trp113Arg	missense_variant	3/10		NM_000237.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

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

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

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

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperlipidemia, familial combined, LPL related

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 02, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.337T>C;p.(Trp113Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1540; PMID: 1479292; 28951076; 1598907) - PS4. The variant is present at low allele frequencies population databases (rs118204069 - gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Trp113Arg) was detected in trans with a pathogenic variant (PMID: 1479292; 28951076; 1598907) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 1598907) - PP1. 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. -

Hyperlipoproteinemia, type I

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1992

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LPL function (PMID: 1598907, 27097985). 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: 1540). This variant is also known as p.Trp86Arg. This missense change has been observed in individual(s) with clinical features of lipoprotein lipase deficiency (PMID: 1598907, 28951076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs118204069, gnomAD 0.007%). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 113 of the LPL protein (p.Trp113Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;D;D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;T;.;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

.;.;H;H

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-14

D;D;D;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

.;.;D;D

Vest4

1.0

MutPred

0.98

.;Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);

MVP

1.0

MPC

0.58

ClinPred

1.0

GERP RS

5.9

Varity_R

0.99

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