chr8-19954168-G-A

Position:

chr8-19954168-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5

The NM_000237.3(LPL):c.590G>A(p.Arg197His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,002 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197C) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 2.08

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000237.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-19954167-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1471786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

PP5

Variant 8-19954168-G-A is Pathogenic according to our data. Variant chr8-19954168-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521082.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.590G>A	p.Arg197His	missense_variant	5/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.590G>A	p.Arg197His	missense_variant	5/10		NM_000237.3	P1
LPL	ENST00000520959.5 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251436

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

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:

0.0000178

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 197 of the LPL protein (p.Arg197His). This variant is present in population databases (rs372668179, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 25966443; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 521082). 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 not expected to disrupt LPL protein function with a negative predictive value of 80%. This variant disrupts the p.Arg197 amino acid residue in LPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12839295, 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2021

The p.R197H pathogenic mutation (also known as c.590G>A), located in coding exon 5 of the LPL gene, results from a G to A substitution at nucleotide position 590. The arginine at codon 197 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with familial chylomicronemia syndrome (FCS) who were homozygous for this alteration or compound heterozygous for an additional alteration in LPL (Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86; Hu X et al. Gene, 2021 Feb;768:145310; Ambry internal data). Furthermore, individuals who were heterozygous for this alteration were identified to have hypertriglyceridemia without an additional alteration identified in LPL (Wright WT et al. Atherosclerosis, 2008 Jul;199:187-92; Surendran RP et al. J Intern Med, 2012 Aug;272:185-96). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 03, 2022

Variant summary: LPL c.590G>A (p.Arg197His) results in a non-conservative amino acid change located in the Lipase/vitellogenin domain (IPR013818) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251436 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (0.0034), allowing no conclusion about variant significance. c.590G>A has been reported in the literature in at least two compound heterozygous individuals affected with severe hypertriglyceridaemia, who carried probably pathogenic missense variants in trans (example, Rabacchi_2015, Hu_2021), and was also reported in individuals with hypertriglyceridaemia a where a second variant was not specified (Wright_2008, Surendran_2012). It has recently been reported as a heterozygous genotype combined with a different heterozygous LMF1 gene variant (c.1523C>T, p.Pro508Leu) in a family Hypertriglyceridemia with authors suggesting that severe hyptertriglyceridemia was of digenic origin caused by LMF1 and LPL double heterozygosity (Guo_2022). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same amino acid, c.590G>T (p.Arg197Leu), was reported in homozygous individuals affected with severe hypertriglyceridemia (Rabacchi_2015), suggesting that Arg197 could be important for protein function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, one as likely pathogenic and one as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hyperlipidemia, familial combined, LPL related

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Jan 22, 2020

The p.Arg197His variant in LPL has been reported in at least 3 individuals (including 1 individual from Northern Ireland and 1 individual from the Netherlands) with Familial Hyperlipidemia (PMID: 28267856, 22239554, 18068174, 25966443), and has been identified in 0.03951% (14/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs372668179). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 521082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two missense variants (p.Arg197Leu and p.Arg197Cys) with a different amino acid change at the same position have been reported in association with disease in the literature (PMID: 25966443, 28267856). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PM5_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.89

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.1

D;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.055

T;.

Polyphen

1.0

D;D

Vest4

0.85

MVP

0.97

MPC

0.49

ClinPred

0.88

GERP RS

6.2

Varity_R

0.75

gMVP

0.92

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