8-19960948-A-T

Variant names:

• chr8-19960948-A-T
• rs886037775
• NM_000237.3:c.1187A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000237.3(LPL):​c.1187A>T​(p.Glu396Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.05

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 8-19960948-A-T is Pathogenic according to our data. Variant chr8-19960948-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226450.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.1187A>T	p.Glu396Val	missense_variant	Exon 8 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.1187A>T	p.Glu396Val	missense_variant	Exon 8 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1	n.*10A>T		non_coding_transcript_exon_variant	Exon 2 of 4			ENSP00000497560.1
LPL	ENST00000650478.1	n.*10A>T		3_prime_UTR_variant	Exon 2 of 4			ENSP00000497560.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperlipoproteinemia, type I Pathogenic:1

Oct 29, 2015

Department of Endocrinology, The Affiliated hospital of QingDao University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I Pathogenic:1

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Oct 27, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1187A>T (p.E396V) alteration is located in coding exon 8 of the LPL gene. This alteration results from a A to T substitution at nucleotide position 1187, causing the glutamic acid (E) at amino acid position 396 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a compound heterozygous finding in a Chinese patient with severe hyperlipidemia and recurrent pancreatitis (Lun, 2017). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not specified Uncertain:1

Apr 11, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LPL c.1187A>T (p.Glu396Val) results in a non-conservative amino acid change located in the PLAT/LH2 domain (IPR001024) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251382 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1187A>T has been reported in the literature in individuals affected with Familial Lipoprotein Lipase Deficiency (e.g., Lun_2017, Zhang_2023), however was also identified in healthy controls (e.g., Cui_2014). These reports do not provide unequivocal conclusions about association of the variant with Familial Lipoprotein Lipase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant may result in reduced transport of LPL to the cell surface relative to wild type (e.g., Lun_2017). The following publications have been ascertained in the context of this evaluation (PMID: 25034063, 28548960, 36991406). ClinVar contains an entry for this variant (Variation ID: 226450). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.71		Loss of catalytic residue at E396 (P = 0.0783);Loss of catalytic residue at E396 (P = 0.0783);
MVP		0.93
MPC		0.43
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.65

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: rs886037775; hg19: chr8-19818459;