rs118204060
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000237.3(LPL):c.701C>T(p.Pro234Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,972 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P234P) has been classified as Likely benign.
Frequency
Consequence
NM_000237.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LPL | NM_000237.3 | c.701C>T | p.Pro234Leu | missense_variant | 5/10 | ENST00000650287.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LPL | ENST00000650287.1 | c.701C>T | p.Pro234Leu | missense_variant | 5/10 | NM_000237.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251454Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135898
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727244
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74292
ClinVar
Submissions by phenotype
Hyperlipoproteinemia, type I Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 14, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.701C>T;p.(Pro234Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1527; OMIM: 609708.0009; PMID: 8099055; 1511985; 2038366) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 8099055) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Lipase) - PM1. The variant is present at low allele frequencies population databases (rs118204060– gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Pro234Leu) was detected in trans with a pathogenic variant (PMID: 8099055) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 8099055; 1511985) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jun 06, 2022 | ACMG classification criteria: PS4 strong, PM2 moderated, PM3 strong, PP3 supporting - |
Hyperlipidemia, familial combined, LPL related Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 05, 2018 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2022 | Reported as the most prevalent founder mutation in the French Canadaian population (Normand et al., 1992; Wood et al., 1993; Bijvoet et al., 1996); Published functional studies suggest impaired LPL activity in transfected cells (Ma et al., 1991).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 30150141, 32041611, 2038366, 24366202, 29748148, 8099055, 8728325, 27055971, 17560523, 1511985) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 234 of the LPL protein (p.Pro234Leu). This variant is present in population databases (rs118204060, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 2038366, 24366202, 29748148, 30150141). ClinVar contains an entry for this variant (Variation ID: 1527). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2019 | The p.P234L pathogenic mutation (also known as c.701C>T), located in coding exon 5 of the LPL gene, results from a C to T substitution at nucleotide position 701. The proline at codon 234 is replaced by leucine, an amino acid with similar properties. This variant (also referred to as P207L) has been reported as a French Canadian founder mutation and has been detected in the homozygous and compound heterozygous state in numerous individuals with familial chylomicronemia syndrome with reduced lipoprotein lipase enzyme activity (Ma Y et al. N. Engl. J. Med., 1991 Jun;324:1761-6; Yang Y et al. J Genet Genomics, 2007 May;34:381-91; Sacks FM et al. JAMA Intern Med, 2014 Mar;174:443-7; Ariza MJ et al. J Clin Lipidol 2018 Aug;12:1482-1492.e3; Hegele RA et al. J Clin Lipidol 2018 Apr;12:920-927.e4; Normand T et al. Hum. Genet., 1992 Aug;89:671-5). This variant has also been detected in the heterozygous state in individuals with hypertriglyceridemia (Yang Y et al. J Genet Genomics, 2007 May;34:381-91). This mutation has been reported to result in a catalytically defective protein with abnormal conformation (Ma Y et al. N. Engl. J. Med., 1991 Jun;324:1761-6; Peterson J et al. J. Lipid Res., 2002 Mar;43:398-406). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
LPL-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 06, 2024 | The LPL c.701C>T variant is predicted to result in the amino acid substitution p.Pro234Leu. This variant has been reported in the homozygous or compound heterozygous state in multiple patients with lipoprotein lipase deficiency and familial chylomicronemia syndrome (FCS) (Hegele et al. 2018. PubMed ID: 29748148; Ariza et al. 2018. PubMed ID: 30150141; Rodrigues et al. 2016. PubMed ID: 27055971). This variant is also a common cause of lipoprotein lipase deficiency among French Canadians, and functional data indicate the p.Pro234Leu substitution reduces LPL protein activity significantly (Ma et al. 1991. PubMed ID: 2038366). In summary, we interpret this variant as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at