rs118204062

Positions:

chr8-19955874-G-A

Variant summary

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

The NM_000237.3(LPL):c.809G>A(p.Arg270His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,004 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R270C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-19955873-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 8-19955874-G-A is Pathogenic according to our data. 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. Variant chr8-19955874-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.809G>A	p.Arg270His	missense_variant	6/10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.809G>A	p.Arg270His	missense_variant	6/10		NM_000237.3	ENSP00000497642	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000398

AC:

AN:

251284

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135802

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727236

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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/Likely 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	DASA	Jan 05, 2022	The c.809G>A;p.(Arg270His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1530; OMIM: 609708.0011; PMID: 23484243; 25966443; 7906986) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 1752947) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Lipase) - PM1. The variant is present at low allele frequencies population databases (rs118204062– gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg270His) was detected in trans with a pathogenic variant (PMID: 25966443) - PM3. Pathogenic missense variant in this residue have been reported (ClinVar ID: 1548; PMID: 29153744) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 25966443; 23484243) - PP1_strong. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2022	Variant summary: LPL c.809G>A (p.Arg270His) results in a non-conservative amino acid change located in the Lipase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251284 control chromosomes. c.809G>A has been reported in the literature in multiple individuals affected with Familial Lipoprotein Lipase Deficiency in the homozygous and compound heterozygous state (Gotoda_1991, Ishimura-Oka_1992, Suzuki_2016). These data indicate that the variant is very likely to be associated with disease. Expression studies have shown the variant to have no detectable enzymatic activity (Gotoda_1991, Ishimura-Oka_1992). Other variants affecting the same codon have been reported in association with Lipoprotein lipase deficiency and Hypertriglyceridaemia (R270C, R270G, R270L; HGMD). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classified the variant as pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1994	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 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: 7906986, 25966443, 29153744). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects LPL function (PMID: 1752947). 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: 1530). This variant is also known as p.Arg243His. This missense change has been observed in individuals with clinical features of lipoprotein lipase deficiency (PMID: 7906986, 23484243, 25966443). This variant is present in population databases (rs118204062, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 270 of the LPL protein (p.Arg270His). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a decreased levels of LPL mass in media and non-detectable enzymatic activity in transfected cells (Gotoda et al., 1991).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R243H); This variant is associated with the following publications: (PMID: 27055971, 7906986, 23484243, 1752947, 27153815, 1702428, 1619366, 32041611, 33303402, 23337350) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hyperlipidemia, familial combined, LPL related

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Aug 05, 2024

The p.Arg270His variant in LPL has been reported in 6 individuals (Dutch, Italian, Japanese, and Chinese) with familial combined hyperlipidemia (PMID: 22239554, 29748148, 25966443, 1752947, 7906986), and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204062). This variant has also been reported in ClinVar as pathogenic (Variation ID: 1530). In vitro functional studies provide some evidence that the p.Arg270His variant may impact protein function (PMID: 1752947). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3, PM2 (Richards 2015). -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2022

The p.R270H pathogenic mutation (also known as c.809G>A), located in coding exon 6 of the LPL gene, results from a G to A substitution at nucleotide position 809. The arginine at codon 270 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in homozygous and compound heterozygous patients with severe hypertriglyceridemia and chylomicronemia (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64; Ma Y et al. Hum Mutat, 1994;3:52-8; Behar DM et al. Isr Med Assoc J, 2013 Jan;15:53-4). In vitro studies have found this mutation impairs LPL protein function (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64). 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

0.94

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.98

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

MVP

1.0

MPC

0.49

ClinPred

1.0

GERP RS

6.1

Varity_R

0.93

gMVP

0.96

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