rs11542065

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000237.3(LPL):c.213C>G(p.His71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,614,130 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H71H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00031 ( 2 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.357

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012491375).

BP6

Variant 8-19948304-C-G is Benign according to our data. Variant chr8-19948304-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 495743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.213C>G	p.His71Gln	missense_variant	2/10	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.213C>G	p.His71Gln	missense_variant	2/10		NM_000237.3	ENSP00000497642	P1

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

503

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000839

AC:

211

AN:

251448

Hom.:

AF XY:

0.000677

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000313

AC:

458

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

207

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.00331

AC:

504

AN:

152274

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0117

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.00340

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00113

AC:

137

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 33303402, 22129523) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 05, 2024

Variant summary: LPL c.213C>G (p.His71Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 251790 control chromosomes, predominantly at a frequency of 0.013 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency phenotype (0.0034). one study identified the variant in 9 of 208 patients with familial hyperlipidemia but did not detect the variant in 171 control individuals, revealing an enrichment of the variant in patients (odds ratio of 16.33 [95% CI = 0.94 - 282.7], Minicocci_2015)(As calculated using the online OR calculator tool, MEDCALC using the case controls data published in Minicocci_Athero_2015). As the 95% CI overlaps 1 there is little confidence in the strength of this assertion and additional large studies would be needed to validate this finding. This variant was also reported in two more individuals from a cohort of hypertriglyceridemia, without primary information (Deshotels_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Lipoprotein Lipase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36325899, 26342331). ClinVar contains an entry for this variant (Variation ID: 495743). Based on the evidence outlined above, the variant was classified as likely benign. -

Hyperlipoproteinemia, type I

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 10, 2020

- -

LPL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.39

T;.;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.72

T;T;.;T

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.39

.;.;N;N

MutationTaster

Benign

0.53

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.94

N;N;N;.

REVEL

Benign

0.20

Sift

Benign

0.31

T;T;T;.

Sift4G

Benign

0.28

T;T;T;.

Polyphen

0.0010

.;.;B;B

Vest4

0.14

MutPred

0.11

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.83

MPC

0.078

ClinPred

0.0020

GERP RS

-0.065

Varity_R

0.34

gMVP

0.41

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