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
Consequence
NM_000237.3 missense
Scores
Clinical Significance
Conservation
Publications
- familial lipoprotein lipase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- hyperlipidemia, familial combined, LPL relatedInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
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ACMG classification
Our verdict: Benign. The variant received -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LPL | NM_000237.3 | c.1136C>T | p.Thr379Ile | missense_variant | Exon 7 of 10 | ENST00000650287.1 | NP_000228.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LPL | ENST00000650287.1 | c.1136C>T | p.Thr379Ile | missense_variant | Exon 7 of 10 | NM_000237.3 | ENSP00000497642.1 | |||
LPL | ENST00000650478.1 | n.80-1524C>T | intron_variant | Intron 1 of 3 | ENSP00000497560.1 |
Frequencies
GnomAD3 genomes AF: 0.00125 AC: 190AN: 152232Hom.: 1 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00173 AC: 434AN: 251148 AF XY: 0.00172 show subpopulations
GnomAD4 exome AF: 0.00129 AC: 1882AN: 1461772Hom.: 3 Cov.: 32 AF XY: 0.00125 AC XY: 909AN XY: 727184 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00125 AC: 190AN: 152350Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120AN XY: 74504 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:3
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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. -
This variant is associated with the following publications: (PMID: 27055971, 8843465) -
Hyperlipoproteinemia, type I Uncertain:1Benign:1
- -
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at