Submissions for variant NM_000237.3(LPL):c.701C>T (p.Pro234Leu)

gnomAD frequency: 0.00001  dbSNP: rs118204060

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253353	SCV001429024	pathogenic	Hyperlipidemia, familial combined, LPL related	2018-12-05	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000001591	SCV001433296	pathogenic	Hyperlipoproteinemia, type I	2019-02-14	criteria provided, single submitter	clinical testing
DASA	RCV000001591	SCV002061255	pathogenic	Hyperlipoproteinemia, type I	2022-01-05	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851555	SCV002240302	pathogenic	not provided	2024-12-02	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Mendelics	RCV001253353	SCV002517578	pathogenic	Hyperlipidemia, familial combined, LPL related	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362550	SCV002666908	pathogenic	Cardiovascular phenotype	2019-11-04	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001851555	SCV002757546	likely pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	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)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000001591	SCV003807004	pathogenic	Hyperlipoproteinemia, type I	2022-06-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderated, PM3 strong, PP3 supporting
Fulgent Genetics, Fulgent Genetics	RCV005049309	SCV005681705	pathogenic	Hyperlipidemia, familial combined, LPL related; Hyperlipoproteinemia, type I	2024-06-19	criteria provided, single submitter	clinical testing
OMIM	RCV000001591	SCV000021747	pathogenic	Hyperlipoproteinemia, type I	1993-05-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003964785	SCV004783490	pathogenic	LPL-related disorder	2024-02-06	no assertion criteria provided	clinical testing	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.