rs372668179
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5
The NM_000237.3(LPL):c.590G>A(p.Arg197His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,002 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000237.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LPL | NM_000237.3 | c.590G>A | p.Arg197His | missense_variant | 5/10 | ENST00000650287.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LPL | ENST00000650287.1 | c.590G>A | p.Arg197His | missense_variant | 5/10 | NM_000237.3 | P1 | ||
LPL | ENST00000520959.5 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251436Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135890
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 197 of the LPL protein (p.Arg197His). This variant is present in population databases (rs372668179, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of chylomicronemia (PMID: 25966443; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 521082). 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 not expected to disrupt LPL protein function with a negative predictive value of 80%. This variant disrupts the p.Arg197 amino acid residue in LPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12839295, 25966443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2021 | The p.R197H pathogenic mutation (also known as c.590G>A), located in coding exon 5 of the LPL gene, results from a G to A substitution at nucleotide position 590. The arginine at codon 197 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with familial chylomicronemia syndrome (FCS) who were homozygous for this alteration or compound heterozygous for an additional alteration in LPL (Rabacchi C et al. Atherosclerosis, 2015 Jul;241:79-86; Hu X et al. Gene, 2021 Feb;768:145310; Ambry internal data). Furthermore, individuals who were heterozygous for this alteration were identified to have hypertriglyceridemia without an additional alteration identified in LPL (Wright WT et al. Atherosclerosis, 2008 Jul;199:187-92; Surendran RP et al. J Intern Med, 2012 Aug;272:185-96). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 03, 2022 | Variant summary: LPL c.590G>A (p.Arg197His) results in a non-conservative amino acid change located in the Lipase/vitellogenin domain (IPR013818) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251436 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (0.0034), allowing no conclusion about variant significance. c.590G>A has been reported in the literature in at least two compound heterozygous individuals affected with severe hypertriglyceridaemia, who carried probably pathogenic missense variants in trans (example, Rabacchi_2015, Hu_2021), and was also reported in individuals with hypertriglyceridaemia a where a second variant was not specified (Wright_2008, Surendran_2012). It has recently been reported as a heterozygous genotype combined with a different heterozygous LMF1 gene variant (c.1523C>T, p.Pro508Leu) in a family Hypertriglyceridemia with authors suggesting that severe hyptertriglyceridemia was of digenic origin caused by LMF1 and LPL double heterozygosity (Guo_2022). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same amino acid, c.590G>T (p.Arg197Leu), was reported in homozygous individuals affected with severe hypertriglyceridemia (Rabacchi_2015), suggesting that Arg197 could be important for protein function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, one as likely pathogenic and one as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Hyperlipidemia, familial combined, LPL related Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg197His variant in LPL has been reported in at least 3 individuals (including 1 individual from Northern Ireland and 1 individual from the Netherlands) with Familial Hyperlipidemia (PMID: 28267856, 22239554, 18068174, 25966443), and has been identified in 0.03951% (14/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs372668179). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 521082). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two missense variants (p.Arg197Leu and p.Arg197Cys) with a different amino acid change at the same position have been reported in association with disease in the literature (PMID: 25966443, 28267856). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PM5_Supporting (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at