rs118204061

chr8-19954240-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 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. I221F) 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:9 U:1
• Conservation: PhyloP100: 7.63

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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 chr8-19954239-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066136.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 id is 1529.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=2, Uncertain_significance=1}. Variant chr8-19954240-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3	c.662T>C	p.Ile221Thr	missense_variant	5/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1	c.662T>C	p.Ile221Thr	missense_variant	5/10		NM_000237.3	P1

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

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251462 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135904

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00

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

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000621 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:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperlipoproteinemia, type I Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1991	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2020	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. -

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

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2023

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. -

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
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	A
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

Publications

LitVar

Other links and lift over

dbSNP: rs118204061; hg19: chr8-19811751;