8-19954333-T-C

Variant names:

• chr8-19954333-T-C
• rs118204080
• NM_000237.3:c.755T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000237.3(LPL):​c.755T>C​(p.Ile252Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,461,744 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I252M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.28
• Publications: 9 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 13 ACMG points.

• PM1: In a region_of_interest Essential for determining substrate specificity (size 23) in uniprot entity LIPL_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000237.3
• 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, 0.869
• PP5: Variant 8-19954333-T-C is Pathogenic according to our data. Variant chr8-19954333-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.755T>C	p.Ile252Thr	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.755T>C	p.Ile252Thr	missense_variant	Exon 5 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000520959.5	c.*182T>C		downstream_gene_variant		4		ENSP00000428496.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251364 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111884

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000248 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperlipoproteinemia, type I Pathogenic:4

Jul 24, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 24, 2022

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.755T>C (p.Ile252Thr) results in a non-conservative amino acid change located in the Lipase domain (IPR013818) 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 2e-05 in 251364 control chromosomes. c.755T>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Familial Lipoprotein Lipase Deficiency (example, Henderson_1998, Evans_2011, Rabacchi_2015, Rodrigues_2016). In one of the compound heterozygous probands, it occurred as a de-novo variant on the maternal allele (Henderson_1998). At least one publication reports experimental evidence evaluating an impact on protein function (Henderson_1993). The most pronounced variant effect results in <10% of normal lipoprotein lipase activity in vitro. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 14, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.755T>C;p.(Ile252Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1554; PMID: 28267856; 9714430) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 8228642; 9714430) - PS3_supporting. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 9714430) - PS2.The variant is present at low allele frequencies population databases (rs118204080– gnomAD 0.0001989%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 9714430) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided Pathogenic:1

Oct 14, 2023

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 252 of the LPL protein (p.Ile252Thr). This variant is present in population databases (rs118204080, gnomAD 0.004%). This missense change has been observed in individual(s) with chylomicronemia and complete absence of LPL activity in plasma (PMID: 8228642, 9714430; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.929T>C p.Ile225Thr. ClinVar contains an entry for this variant (Variation ID: 1554). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 8228642). For these reasons, this variant has been classified as Pathogenic. -

Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I Pathogenic:1

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.1	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.64	P;P
Vest4		0.93
MVP		0.93
MPC		0.29
ClinPred		0.80	D
GERP RS		6.2
Varity_R		0.85
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

Other links and lift over

dbSNP: rs118204080; hg19: chr8-19811844;