rs268

Positions:

chr8-19956018-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000237.3(LPL):c.953A>G(p.Asn318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,614,214 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 14 hom., cov: 32)

Exomes 𝑓: 0.016 ( 229 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:10B:6O:1

Conservation

PhyloP100: 2.93

Variant links:

Genes affected

LPL (HGNC:6677): (lipoprotein lipase) LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

LPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009144157).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1936/152336) while in subpopulation NFE AF= 0.0186 (1264/68028). AF 95% confidence interval is 0.0177. There are 14 homozygotes in gnomad4. There are 968 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.953A>G	p.Asn318Ser	missense_variant	6/10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.953A>G	p.Asn318Ser	missense_variant	6/10		NM_000237.3	ENSP00000497642	P1
LPL	ENST00000650478.1 linkuse as main transcript	c.14A>G	p.Asn5Ser	missense_variant, NMD_transcript_variant	1/4			ENSP00000497560

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1936

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.0128

AC:

3212

AN:

251336

Hom.:

AF XY:

0.0124

AC XY:

1688

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00674

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0160

AC:

23443

AN:

1461878

Hom.:

229

Cov.:

AF XY:

0.0157

AC XY:

11445

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.00671

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00243

Gnomad4 FIN exome

AF:

0.0206

Gnomad4 NFE exome

AF:

0.0186

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0127

AC:

1936

AN:

152336

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

968

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.0163

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0225

Gnomad4 NFE

AF:

0.0186

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0187

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0184

AC:

158

ExAC

AF:

0.0134

AC:

1622

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0170

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:10Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type I

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Jan 04, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2019	- -

not provided

Pathogenic:1Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2022	- -
Likely pathogenic, flagged submission	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 24, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hyperlipidemia, familial combined, LPL related

Pathogenic:1Uncertain:2

Pathogenic, flagged submission	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 03, 2023	_x000D_ Criteria applied: PS3_SUP, PM5_SUP -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 02, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2022	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. -

Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Dec 22, 2020

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2019

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. -

Hyperlipidemia, familial combined, susceptibility to

Other:1

risk factor, flagged submission

literature only

OMIM

Sep 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

0.011

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

.;D

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

-0.096

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;.

REVEL

Uncertain

0.31

Sift

Benign

0.25

T;.

Sift4G

Benign

0.17

T;.

Polyphen

0.10

B;B

Vest4

0.049

MPC

0.066

ClinPred

0.033

GERP RS

6.1

Varity_R

0.29

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over