ClinVar Miner

Submissions for variant NM_000237.3(LPL):c.755T>C (p.Ile252Thr)

gnomAD frequency: 0.00002  dbSNP: rs118204080
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001039273 SCV001202796 pathogenic not provided 2023-10-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 252 of the LPL protein (p.Ile252Thr). This variant is present in population databases (rs118204080, gnomAD 0.004%). This missense change has been observed in individual(s) with chylomicronemia and complete absence of LPL activity in plasma (PMID: 8228642, 9714430; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.929T>C p.Ile225Thr. ClinVar contains an entry for this variant (Variation ID: 1554). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 8228642). For these reasons, this variant has been classified as Pathogenic.
DASA RCV000001619 SCV002061291 pathogenic Hyperlipoproteinemia, type I 2022-01-05 criteria provided, single submitter clinical testing The c.755T>C;p.(Ile252Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 1554; PMID: 28267856; 9714430) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 8228642; 9714430) - PS3_supporting. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 9714430) - PS2.The variant is present at low allele frequencies population databases (rs118204080– gnomAD 0.0001989%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 9714430) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001619 SCV002819785 pathogenic Hyperlipoproteinemia, type I 2022-12-24 criteria provided, single submitter clinical testing Variant summary: LPL c.755T>C (p.Ile252Thr) results in a non-conservative amino acid change located in the Lipase domain (IPR013818) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251364 control chromosomes. c.755T>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Familial Lipoprotein Lipase Deficiency (example, Henderson_1998, Evans_2011, Rabacchi_2015, Rodrigues_2016). In one of the compound heterozygous probands, it occurred as a de-novo variant on the maternal allele (Henderson_1998). At least one publication reports experimental evidence evaluating an impact on protein function (Henderson_1993). The most pronounced variant effect results in <10% of normal lipoprotein lipase activity in vitro. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005041965 SCV005681706 likely pathogenic Hyperlipidemia, familial combined, LPL related; Hyperlipoproteinemia, type I 2024-06-10 criteria provided, single submitter clinical testing
OMIM RCV000001619 SCV000021775 pathogenic Hyperlipoproteinemia, type I 1998-07-24 no assertion criteria provided literature only
Natera, Inc. RCV000001619 SCV002083212 pathogenic Hyperlipoproteinemia, type I 2021-09-14 no assertion criteria provided clinical testing

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