rs11542065

chr8-19948304-C-Gchr8-19948304-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H71H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.357

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495743.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3	c.213C>G	p.His71Gln	missense_variant	2/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1	c.213C>G	p.His71Gln	missense_variant	2/10		NM_000237.3	P1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152156 Hom.: 1 Cov.: 31

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.: 0 AF XY: 0.000677 AC XY: 92 AN XY: 135892

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.: 2 Cov.: 31 AF XY: 0.000285 AC XY: 207 AN XY: 727230

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.: 1 Cov.: 31 AF XY: 0.00352 AC XY: 262 AN XY: 74460

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.: 0

Bravo AF: 0.00340

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00113 AC: 137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 33303402, 22129523) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 02, 2017	Variant summary: The LPL c.213C>G (p.His71Gln) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution in the Alpha/Beta hydrolase fold, the Lipase/vitellogenin, and Lipase, N-terminal domains (InterPro). 3/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC in 137 of 121740 control chromosomes from all ethnicities, but was predominantly observed in the African subpopulation at a frequency of 0.012973 (135/10406). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. However, 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])(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. Furthermore, based upon the authors own assertion, that this variant is non-pathogenic, and its higher frequency in controls, this variant is classified as a VUS-Possibly Benign until additional evidence supporting an alternative outcome are obtained. -

Hyperlipoproteinemia, type I Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 10, 2020

- -

LPL-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	13
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	D
LIST_S2	Benign	0.72	T;T;.;T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	0.53	D
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs11542065; hg19: chr8-19805815;