NM_000237.3:c.1187A>T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• familial lipoprotein lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics
• hyperlipidemia, familial combined, LPL related

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.
• 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 VariationId is 226450.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000237.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.1187A>T	p.Glu396Val	missense	Exon 8 of 10	NP_000228.1	P06858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000650287.1	MANE Select	c.1187A>T	p.Glu396Val	missense	Exon 8 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.1187A>T	p.Glu396Val	missense	Exon 10 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.1184A>T	p.Glu395Val	missense	Exon 8 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I (1)
1	-	-	Hyperlipoproteinemia, type I (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.1
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
Vest4		0.61
MutPred		0.71		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

Other links and lift over

dbSNP: rs886037775; hg19: chr8-19818459;