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

gnomAD frequency: 0.01327  dbSNP: rs268

Total submissions: 19

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
Labcorp Genetics (formerly Invitae), Labcorp	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: seen in unaffected individuals, 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	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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002222335	SCV004847366	likely benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	The p.Asn318Ser variant in LPL is classified as likely benign because it has been identified in 2.3% (239/10624) of European chromosomes by gnomAD including 14 total homozygotes (http://gnomad.broadinstitute.org, v.3). ACMG/AMP Criteria applied: BS1.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000988041	SCV005045002	uncertain significance	Hyperlipoproteinemia, type I	2024-01-04	criteria provided, single submitter	clinical testing	The LPL c.953A>G (p.Asn318Ser) variant, also reported as p.Asn291Ser, has been reported in multiple individuals as a risk factor for familial combined hyperlipidemia (Berg SM et al., PMID: 28502509; Hoffer MJ et al., PMID: 8808493; Lopez-Ruiz A et al., PMID: 19335919; Reymer PW et al., PMID: 8541837; Syvanne M et al., PMID: 8732773). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 2.1 % in the European Finnish population which is higher than the incidence of disease (1-2% in the general population). Computational predictors are uncertain as to the impact of this variant on LPL function. This variant has been reported in the ClinVar database as a germline variant, ranging from benign to likely pathogenic. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
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