8-19959377-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_000237.3(LPL):​c.1136C>T​(p.Thr379Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,122 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign 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. T379A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.492

Publications

5 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.010416418).
BP6
Variant 8-19959377-C-T is Benign according to our data. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742. Variant chr8-19959377-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495742.
BS2
High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LPLNM_000237.3 linkc.1136C>T p.Thr379Ile missense_variant Exon 7 of 10 ENST00000650287.1 NP_000228.1 P06858A0A1B1RVA9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LPLENST00000650287.1 linkc.1136C>T p.Thr379Ile missense_variant Exon 7 of 10 NM_000237.3 ENSP00000497642.1 P06858
LPLENST00000650478.1 linkn.80-1524C>T intron_variant Intron 1 of 3 ENSP00000497560.1 A0A3B3IT60

Frequencies

GnomAD3 genomes
AF:
0.00125
AC:
190
AN:
152232
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00885
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00121
Gnomad OTH
AF:
0.000957
GnomAD2 exomes
AF:
0.00173
AC:
434
AN:
251148
AF XY:
0.00172
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00852
Gnomad NFE exome
AF:
0.00201
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00129
AC:
1882
AN:
1461772
Hom.:
3
Cov.:
32
AF XY:
0.00125
AC XY:
909
AN XY:
727184
show subpopulations
African (AFR)
AF:
0.000269
AC:
9
AN:
33478
American (AMR)
AF:
0.000112
AC:
5
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00852
AC:
455
AN:
53382
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00123
AC:
1363
AN:
1111970
Other (OTH)
AF:
0.000828
AC:
50
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
94
189
283
378
472
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
48
96
144
192
240
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00125
AC:
190
AN:
152350
Hom.:
1
Cov.:
32
AF XY:
0.00161
AC XY:
120
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.000192
AC:
8
AN:
41582
American (AMR)
AF:
0.000261
AC:
4
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00885
AC:
94
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00121
AC:
82
AN:
68038
Other (OTH)
AF:
0.000947
AC:
2
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
9
17
26
34
43
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000869
Hom.:
0
Bravo
AF:
0.000453
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.00191
AC:
232
EpiCase
AF:
0.000763
EpiControl
AF:
0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 08, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: The LPL c.1136C>T (p.Thr379Ile) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 232/121442 control chromosomes (1 homozygote) from ExAC, relatively more commonly observed in the European (Finnish) subpopulation at a frequency of 0.006408 (42/6554). This frequency in European (Finnish) is about 2 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. The variant was identified in at least 1 patient with hypertriglyceridemia without strong evidence for pathogenicity (Surendran_2012). Taken together, this variant is classified as Likely Benign. -

Jun 21, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27055971, 8843465) -

Hyperlipoproteinemia, type I Uncertain:1Benign:1
Jan 23, 2020
Natera, Inc.
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Benign:1
Aug 08, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

LPL-related disorder Benign:1
Oct 21, 2020
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.096
N
LIST_S2
Benign
0.85
.;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.010
T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.9
L;L
PhyloP100
0.49
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-2.4
N;.
REVEL
Uncertain
0.34
Sift
Benign
0.043
D;.
Sift4G
Benign
0.21
T;.
Polyphen
0.0090
B;B
Vest4
0.15
MVP
0.81
MPC
0.085
ClinPred
0.013
T
GERP RS
4.0
Varity_R
0.11
gMVP
0.63

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

Other links and lift over

dbSNP: rs76708715; hg19: chr8-19816888; API