Submissions for variant NM_000237.3(LPL):c.808C>T (p.Arg270Cys)

gnomAD frequency: 0.00001  dbSNP: rs118204077

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055155	SCV001219527	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg270 amino acid residue in LPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1752947, 7906986, 25966443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1548). This variant is also known as p.Arg243Cys. This missense change has been observed in individuals with clinical features of lipoprotein lipase deficiency (PMID: 7906986, 25966443, 29153744). This variant is present in population databases (rs118204077, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 270 of the LPL protein (p.Arg270Cys).
DASA	RCV000001613	SCV002061151	pathogenic	Hyperlipoproteinemia, type I	2022-01-05	criteria provided, single submitter	clinical testing	The c.808C>T;p.(Arg270Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1548; PMID: 29153744; 29748148; 9279761; 7906986) - PS4.The variant is present at low allele frequencies population databases (rs118204077– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg270Cys) was detected in trans with a pathogenic variant (PMID: 29153744; 29748148; 7906986) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID: 1530; PMID: 29748148) - PM5. 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.
Ambry Genetics	RCV002415386	SCV002677634	pathogenic	Cardiovascular phenotype	2021-03-25	criteria provided, single submitter	clinical testing	The p.R270C pathogenic mutation (also known as c.808C>T and p.R243C), located in coding exon 6 of the LPL gene, results from a C to T substitution at nucleotide position 808. The arginine at codon 270 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in subjects with features of lipoprotein lipase deficiency (LPL) and has been shown to have an impact on protein function (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64; Rodrigues R et al. J Clin Lipidol Dec;10:394-409; Vidanapathirana DM et al. Glob Pediatr Health, 2017 Jun;4:2333794X17715839; Teramoto R et al. Atherosclerosis, 2018 02;269:272-278; Tada H et al. Clin Chim Acta, 2019 Jan;488:31-39). Other alterations affecting the same amino acid, p.R270H and p.R270G, have also been reported in association with LPL deficiency (Gotoda T et al. J Clin Invest, 1991 12;88:1856-64; Khovidhunkit W et al. J Clin Lipidol Nov;10:505-511.e1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV001055155	SCV003823424	pathogenic	not provided	2022-08-09	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000001613	SCV004048079	pathogenic	Hyperlipoproteinemia, type I		criteria provided, single submitter	clinical testing	The LPL c.808C>T (p.Arg270Cys) variant has been reported in individuals affected with lipoprotein lipase deficiency (Rabacchi et al). This variant disrupts the p.Arg270 amino acid residue in LPL. Other variant(s) that disrupt this residue have been observed in individuals with LPL-related conditions (Gotoda et al., 1991), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been reported to the ClinVar database as Pathogenic. The p.Arg270Cys variant is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 270 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg270Cys in LPL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003894783	SCV004716679	pathogenic	LPL-related disorder	2023-12-26	criteria provided, single submitter	clinical testing	The LPL c.808C>T variant is predicted to result in the amino acid substitution p.Arg270Cys. This variant (aka Arg243Cys) has been previously reported in the heterozygous state, along with second plausible causative variants in the same gene, in two individuals who presented with suspected familial chylomicronemia (Ma et al. 1994. PubMed ID: 7906986). In vitro function studies indicated that the p.Arg270Cys variant resulted in catalytically defective LPL (Ma et al. 1994. PubMed ID: 7906986). This variant was also described in the compound heterozygous or homozygous states state in individuals who presented with familial chylomicronemia (Benlian et al. 1996. PubMed ID: 8778602; Teramoto et al. 2018. PubMed ID: 29153744). Different amino acid changes at this position (p.Arg270Gly, p.Arg270His, and p.Arg270Leu) have also been reported in patients with disease (D’Erasmo et al. 2019. PubMed ID: 31619059, supplementary table 1; Rodrigues et al. 2016. PubMed ID: 27055971). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000001613	SCV000021769	pathogenic	Hyperlipoproteinemia, type I	1994-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000001613	SCV001460450	pathogenic	Hyperlipoproteinemia, type I	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001055155	SCV001921668	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001055155	SCV001963141	pathogenic	not provided		no assertion criteria provided	clinical testing