8-19939443-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Moderate

The NM_000237.3(LPL):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

LPL
NM_000237.3 start_lost

Scores

6
5
5

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.11
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 228 CDS bases. Genomic position: 19948319. Lost 0.160 part of the original CDS.
PS1
Another start lost variant in NM_000237.3 (LPL) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-19939443-G-C is Pathogenic according to our data. Variant chr8-19939443-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3595455.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LPLNM_000237.3 linkc.3G>C p.Met1? start_lost Exon 1 of 10 ENST00000650287.1 NP_000228.1 P06858A0A1B1RVA9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LPLENST00000650287.1 linkc.3G>C p.Met1? start_lost Exon 1 of 10 NM_000237.3 ENSP00000497642.1 P06858

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I Pathogenic:1
Jun 01, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
24
DANN
Uncertain
0.97
DEOGEN2
Benign
0.029
T;.;T;T
Eigen
Benign
0.099
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D;D;.;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Uncertain
-0.027
T
PROVEAN
Benign
-1.6
N;N;N;.
REVEL
Uncertain
0.51
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
0.52
.;.;P;P
Vest4
0.98
MutPred
1.0
Gain of catalytic residue at M1 (P = 0.0571);Gain of catalytic residue at M1 (P = 0.0571);Gain of catalytic residue at M1 (P = 0.0571);Gain of catalytic residue at M1 (P = 0.0571);
MVP
0.92
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.89
gMVP
0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-19796954; API