8-19954240-T-C

Variant names:

• chr8-19954240-T-C
• rs118204061
• NM_000237.3:c.662T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_000237.3(LPL):​c.662T>C​(p.Ile221Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,058 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. I221N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1
• Conservation: PhyloP100: 7.63
• Publications: 15 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 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, 7 uncertain in NM_000237.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-19954240-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2583060.Status of the report is criteria_provided_single_submitter, 1 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, 0.939
• PP5: Variant 8-19954240-T-C is Pathogenic according to our data. Variant chr8-19954240-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1529.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.662T>C	p.Ile221Thr	missense_variant	Exon 5 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.662T>C	p.Ile221Thr	missense_variant	Exon 5 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000520959.5	c.*89T>C		downstream_gene_variant		4		ENSP00000428496.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152174 Hom.: 0 Cov.: 33

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251462 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74346

African (AFR) AF: 0.0000483 AC: 2 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000465 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5

Dec 22, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the LPL gene demonstrated a sequence change, c.662T>C, in exon 5 that results in an amino acid change, p.Ile221Thr. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.002% and a frequency of 0.005% in east Asian sub group (dbSNP rs118204061). This sequence change has been described in individuals with hypertriglyceridemia in the heterozygous state (PMIDs: 21159338, 27055971, 17717288), and in individuals and family with lipoprotein ligase deficiency in the homozygous and compound heterozygous states (PMIDs: 1674945, 22095987, 16972177). The p.Ile221Thr change affects a highly conserved amino acid residue located in a domain of the lipoprotein lipase (LPL) that is known to be functional. Functional study shows p.Ile221Thr disrupts the enzyme activity of LPL (PMID: 1674945). Collectively these evidences indicate that the p.Ile221Thr variant is pathogenic. -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the LPL protein (p.Ile221Thr). This variant is present in population databases (rs118204061, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 1674945, 1702428, 15877202, 25966443). 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 p.Ile194Thr. ClinVar contains an entry for this variant (Variation ID: 1529). 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 expected to disrupt LPL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 1702428). For these reasons, this variant has been classified as Pathogenic. -

Jan 10, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LPL: PM3:Very Strong, PM2, PP3, PS3:Supporting -

Apr 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that I221T results in defective LPL protein and inactive enzyme (Dichek et al., 1991; Henderson et al., 1991; Fojo et al., 1992; Peterson et al., 2002; Ooi et al., 2012; Wang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as I194T; This variant is associated with the following publications: (PMID: 17717288, 30389453, 1505655, 15877202, 16972177, 1702428, 27055971, 27573733, 25966443, 1479292, 11893776, 15256764, 31589614, 32041611, 1674945, 35923617, 22095987, 35820489) -

Hyperlipoproteinemia, type I Pathogenic:4

Jun 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across nine studies, the LPL c.662T>C (p.Ile221Thr) missense variant, which is also referred to as p.Ile194Thr, was identified in 18 subjects with familial lipoprotein lipase deficiency or severe hypertriglyceridemia, including four homozygotes, six compound heterozygotes, and eight heterozygotes in whom a second variant was not identified, and in a heterozygous state in at least two unaffected family members of patients (Henderson et al. 1991; Dichek et al. 1991; Santer et al. 2005; Nierman et al. 2006; Wang et al. 2007; Ooi et al. 2011; Rabacchi et al. 2015; Rodrigues et al. 2016; Tani et al. 2016). The variant was absent from 522 total control individuals in these studies. The variant is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on only one allele in a region of good sequencing coverage so the variant is presumed to be rare in the general population. Functional studies demonstrated that despite finding the variant protein in the culture medium, the variant protein had virtually no lipolytic activity. Further, the amount of intracellular variant LPL protein was found to be higher than wildtype and it is suggested that the variant protein may not be secreted appropriately (Henderson et al. 1991). These results were confirmed in studies by Dichek et al. (1991) and Fojo et al. (1992). Based on the collective evidence, the p.Ile221Thr variant is classified as pathogenic for familial lipoprotein lipase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:2

Aug 03, 2022

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I221T variant (also known as c.662T>C), located in coding exon 5 of the LPL gene, results from a T to C substitution at nucleotide position 662. The isoleucine at codon 221 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as compound heterozygous with known pathogenic mutations in LPL and as homozygous in individuals with familial chylomicronemia syndrome (Dichek HL et al. J Biol Chem, 1991 Jan;266:473-7; Henderson HE et al. J Clin Invest, 1991 Jun;87:2005-11; Reina M et al. J Lipid Res, 1992 Dec;33:1823-32; Nierman MC et al. J Inherit Metab Dis, 2006 Oct;29:686; Ooi EM et al. Arterioscler Thromb Vasc Biol, 2012 Feb;32:459-66; Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86). Additionally, this alteration has been reported as heterozygous in individuals with hypertriglyceridemia (Rodrigues R et al. J Clin Lipidol, 2016 Dec;10:394-409; Wang J et al. Arterioscler Thromb Vasc Biol, 2007 Nov;27:2450-5; Evans D et al. Atherosclerosis, 2011 Feb;214:386-90; Tada H et al. Clin Chim Acta, 2019 Jan;488:31-39). In vitro studies showed this alteration impacts protein function (Fojo SS et al. Eur J Epidemiol, 1992 May;8 Suppl 1:59-63; Peterson J et al. J Lipid Res, 2002 Mar;43:398-406). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hyperlipidemia, familial combined, LPL related Pathogenic:1 Uncertain:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.Ile221Thr variant in LPL has been reported in at least 3 individuals (including South African, German, European origin) with familial combined hyperlipidemia, segregated with disease in 2 affected relatives from 1 family (PMID: 21159338, 17717288, 1674945), and has been identified in 0.005% (1/19954) of East Asian, 0.003% (3/129174) of European (non-Finnish), and 0.003% (1/35440) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118204061). This variant has also been reported in ClinVar as pathogenic (Variation ID: 1529). In vitro functional studies provide some evidence that the p.Ile221Thr variant may impact protein function (PMID: 1505655, 1674945, 11893776). 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. Three affected individuals with this variant have an alternative molecular basis for familial combined hyperlipidemia, suggesting that this variant may not be pathogenic (PMID: 16972177). In summary, the clinical significance of the p.Ile221Thr variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting, PP3, BP5 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		7.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.99
MPC		0.49
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.93
gMVP		0.93

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

Other links and lift over

dbSNP: rs118204061; hg19: chr8-19811751;