8-19954222-G-A

Variant names:

• chr8-19954222-G-A
• rs118204057
• NM_000237.3:c.644G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PP2 PP5_Very_Strong

The NM_000237.3(LPL):​c.644G>A​(p.Gly215Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002061296: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:29288010) - PS3_supporting."; SCV005885183: The most pronounced variant effect results in <10% of normal activity (Emi_1990).; SCV000617843: Functional studies have demonstrated that G215E results in a complete loss of catalytic activity (Hata et al., 1992); SCV000935254: Experimental studies have shown that this missense change affects LPL function (PMID:1400331, 1969408, 29288010).; SCV001422593: "In vitro functional studies provide some evidence that the p.Gly215Glu variant may slightly impact protein function." PMID:1969408, 29288010; SCV001754801: Functional studies show a loss of enzyme activity resulting from this variant (PMID:1400331).; SCV003925391: "In vitro functional studies demonstrated reduced catalytic activity and protein function in HEK293T and COS-1 cells carrying c.644G>A variant." PMID:1400331, 29288010, 1969408; SCV002656807: Functional studies indicate that this alteration results in deficient protein function (Emi, 1990; Hata, 1992; Caddeo, 2018).; SCV004118140: Functional studies also suggest this variant decreases LPL protein activity (Caddeo et al. 2018. PubMed ID: 29288010).". Synonymous variant affecting the same amino acid position (i.e. G215G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 9.48
• Publications: 49 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002061296: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 29288010) - PS3_supporting."; SCV005885183: The most pronounced variant effect results in <10% of normal activity (Emi_1990).; SCV000617843: Functional studies have demonstrated that G215E results in a complete loss of catalytic activity (Hata et al., 1992); SCV000935254: Experimental studies have shown that this missense change affects LPL function (PMID: 1400331, 1969408, 29288010).; SCV001422593: "In vitro functional studies provide some evidence that the p.Gly215Glu variant may slightly impact protein function." PMID:1969408, 29288010; SCV001754801: Functional studies show a loss of enzyme activity resulting from this variant (PMID: 1400331).; SCV003925391: "In vitro functional studies demonstrated reduced catalytic activity and protein function in HEK293T and COS-1 cells carrying c.644G>A variant." PMID: 1400331, 29288010, 1969408; SCV002656807: Functional studies indicate that this alteration results in deficient protein function (Emi, 1990; Hata, 1992; Caddeo, 2018).; SCV004118140: Functional studies also suggest this variant decreases LPL protein activity (Caddeo et al. 2018. PubMed ID: 29288010).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000237.3
• 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.
• PP5: Variant 8-19954222-G-A is Pathogenic according to our data. Variant chr8-19954222-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.644G>A	p.Gly215Glu	missense	Exon 5 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.644G>A	p.Gly215Glu	missense	Exon 5 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.644G>A	p.Gly215Glu	missense	Exon 7 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.641G>A	p.Gly214Glu	missense	Exon 5 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000655

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: 0.000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 251454 AF XY: 0.000191

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000367 AC: 537 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000375 AC XY: 273 AN XY: 727242

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000444 AC: 494 AN: 1112002

Other (OTH) AF: 0.000331 AC: 20 AN: 60396

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74440

African (AFR) AF: 0.0000722 AC: 3 AN: 41534

American (AMR) AF: 0.000654 AC: 10 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Hyperlipoproteinemia, type I (7)
7	-	-	not provided (7)
4	-	-	Hyperlipidemia, familial combined, LPL related (4)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I (1)
1	-	-	LPL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.9	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.70
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.50
ClinPred		0.15	T
GERP RS		5.3
Varity_R		0.44
gMVP		0.92

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: rs118204057; hg19: chr8-19811733;