ClinVar Miner

Submissions for variant NM_000237.3(LPL):c.953A>G (p.Asn318Ser)

gnomAD frequency: 0.01327  dbSNP: rs268
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000001615 SCV000746401 uncertain significance Hyperlipidemia, familial combined, LPL related 2023-12-10 criteria provided, single submitter clinical testing
Mendelics RCV000988041 SCV001137595 uncertain significance Hyperlipoproteinemia, type I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000988041 SCV001324129 uncertain significance Hyperlipoproteinemia, type I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000988041 SCV001433295 uncertain significance Hyperlipoproteinemia, type I 2019-04-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000988041 SCV001653409 uncertain significance Hyperlipoproteinemia, type I 2021-05-18 criteria provided, single submitter clinical testing
Invitae RCV001356263 SCV001718414 benign not provided 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV001356263 SCV001891468 benign not provided 2020-02-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 8732773, 8808493, 32041611, 8872057, 28267856, 26975783, 31619059, 29431110, 28502509, 27055971, 28008009, 7647785, 19335919, 24503134, 20650961, 7607318, 22691586, 24507774, 18922999)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222335 SCV002500376 benign not specified 2022-03-14 criteria provided, single submitter clinical testing Variant summary: LPL c.953A>G (p.Asn318Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.013 in 251336 control chromosomes in the gnomAD database, including 32 homozygotes. The observed variant frequency is approximately 3.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency phenotype (0.0034), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no penetrant association of c.953A>G in individuals affected with Familial Lipoprotein Lipase Deficiency have been reported. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics RCV002371753 SCV002688471 benign Cardiovascular phenotype 2019-01-31 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center RCV002467488 SCV002764538 uncertain significance Hyperlipidemia, familial combined, LPL related; Hyperlipoproteinemia, type I 2020-12-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV001356263 SCV003817054 uncertain significance not provided 2022-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000001615 SCV003925626 uncertain significance Hyperlipidemia, familial combined, LPL related 2023-04-03 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3_SUP, PM5_SUP
OMIM RCV000781944 SCV000021771 risk factor Hyperlipidemia, familial combined, susceptibility to 1995-09-01 flagged submission literature only
Reproductive Health Research and Development, BGI Genomics RCV000001615 SCV001142388 pathogenic Hyperlipidemia, familial combined, LPL related 2020-01-06 flagged submission curation NM_000237.2:c.953A>G in the LPL gene has an allele frequency of 0.021 in European (Finnish) subpopulation in the gnomAD database, including 36 homozygous occurrences. However, since familial combined hyperlipidemia is estimated with a prevalence of 1 in 100, we decided not taken the prevalance and homozygous number in the gnomAD database as a strong benign evidence. This variant also known as Asn291Ser in literatures, has been detected in 11.8% (20/169) of persons affected with familial combined hyperlipidemia (PMID: 8541837). Functional analyses reveal that Asn291Ser mutation in the LPL gene is associated with significantly reduced HDL levels and results in a significant decrease in LPL catalytic activity. Taken together, we interpret it as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS4, PS3.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356263 SCV001551380 uncertain significance not provided no assertion criteria provided clinical testing The LPL p.Asn318Ser variant was identified in dbSNP (ID: rs268), Clinvitae, MutDB, LOVD 3.0 and ClinVar (reported as pathogenic for Hyperapobetalipoproteinemia by Genomics Research Center, Shahid Beheshti University of Medical Sciences), but was not identified in Cosmic. The variant was identified in control databases in 3667 of 282748 chromosomes (36 homozygous) at a frequency of 0.012969 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 521 of 25120 chromosomes (freq: 0.02074), European (non-Finnish) in 2569 of 129068 chromosomes (freq: 0.0199), Other in 96 of 7218 chromosomes (freq: 0.0133), Ashkenazi Jewish in 108 of 10370 chromosomes (freq: 0.01041), Latino in 239 of 35430 chromosomes (freq: 0.006746), African in 77 of 24972 chromosomes (freq: 0.003083) and South Asian in 57 of 30616 chromosomes (freq: 0.001862); it was not observed in the East Asian population. Reymer et al. (1995) identified the p.N318S variant in 20/169 (freq=0.59) heterozygous patients with familial combined hyperlipidemia and 10/215 (freq=0.023) heterozygous controls, with all carriers having decreased HDL-cholesterol levels (Reymer_1995_PMID: 8541837). The p.N318S variant was also identified in the heterozygous state in 6/19 patients of Northern Irish descent with severe hypertriglyceridemia (HTG) and was further found in the heterozygous state in 28/218 HTG patients (12.8%) compared to 13/314 controls (4.1%) (Wright_2008_PMID: 18068174). Surendran et al. (2012) identified the variant in 10/86 heterozygous HTG patients and in 2/86 homozygous HTG patients compared to 4/327 heterozygous controls (Surendran_2012_PMID: 22239554). The p.Asn318 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc. RCV000988041 SCV002083220 benign Hyperlipoproteinemia, type I 2019-11-14 no assertion criteria provided clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV001356263 SCV002501372 likely pathogenic not provided 2022-03-24 flagged submission clinical testing

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