rs372668179

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_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:5U:1

Conservation

PhyloP100: 2.08

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

familial lipoprotein lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
hyperlipidemia, familial combined, LPL related
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

LPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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, 6 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.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.

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 Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.590G>A	p.Arg197His	missense_variant	Exon 5 of 10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 link	c.590G>A	p.Arg197His	missense_variant	Exon 5 of 10		NM_000237.3	ENSP00000497642.1		P06858
LPL	ENST00000520959.5 link	c.*17G>A		downstream_gene_variant		4		ENSP00000428496.1		E7EW14

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

GnomAD2 exomes

AF:

0.0000676

AC:

AN:

251436

AF XY:

0.0000294

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 19, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple individuals with hypertriglyceridemia who were heterozygous or compound heterozygous for the p.(R197H) variant in published literature (PMID: 18068174, 22239554, 25966443, 28267856); Published functional studies suggest this variant results in partial reduction of LPL levels, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 35368694); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22239554, 28267856, 25966443, 32041611, 33217533, 35130036, 35241092, 35368694, 18068174) -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Hyperlipoproteinemia, type I

Pathogenic:1

May 22, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 6.8e-05 in 251436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (6.8e-05 vs 0.0034), allowing no conclusion about variant significance. c.590G>A has been observed in compound heterozygous individual(s) affected with Familial Lipoprotein Lipase Deficiency and in heterozygous individuals with hypertriglyceridemia where no second variant in LPL was reported (e.g. Rabacchi_2015, Hu_2021, Xia_2023, Wright_2008, Surendran_2012, Internal data). These data indicate that the variant is likely to be associated with disease. It has also been reported as a heterozygous genotype combined with a different heterozygous LMF1 gene variant (c.1523C>T, p.Pro508Leu) in a family with hypertriglyceridemia with authors suggesting that severe hyptertriglyceridemia was of digenic origin caused by LMF1 and LPL double heterozygosity (Guo_2022). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Xia_2023). Additionally, a different variant affecting the same codon has been classified as pathogenic in ClinVar (c.590G>T, p.Arg197Leu), supporting the critical relevance of codon 197 to LPL protein function. The following publications have been ascertained in the context of this evaluation (PMID: 33588820, 32041611, 35368694, 33217533, 28267856, 35309119, 25966443, 22239554, 18068174, 37858495). ClinVar contains an entry for this variant (Variation ID: 521082). Based on the evidence outlined above, the variant was classified as pathogenic for Familial Lipoprotein Lipase Deficiency and Hypertriglyceridemia. -

Cardiovascular phenotype

Pathogenic:1

Sep 16, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 variant 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 variant 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 amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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. -

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

Pathogenic:1

Dec 25, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperlipidemia, familial combined, LPL related

Uncertain:1

Jan 22, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

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

(source)

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

PhyloP100

2.1

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

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rs372668179

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over