ClinVar Genomic variation as it relates to human health

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.

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)

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.

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.

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.