rs118204079

Variant names:

• chr8-19962126-G-A
• rs118204079
• NM_000237.3:c.1334G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-19962126-G-A
• chr8-19962126-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000237.3(LPL):​c.1334G>A​(p.Cys445Tyr) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. C445C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.18
• Publications: 11 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: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 8 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, 0.986
• PP5: Variant 8-19962126-G-A is Pathogenic according to our data. Variant chr8-19962126-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1553.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.1334G>A	p.Cys445Tyr	missense_variant	Exon 9 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.1334G>A	p.Cys445Tyr	missense_variant	Exon 9 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1	n.*157G>A		non_coding_transcript_exon_variant	Exon 3 of 4			ENSP00000497560.1
LPL	ENST00000650478.1	n.*157G>A		3_prime_UTR_variant	Exon 3 of 4			ENSP00000497560.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperlipoproteinemia, type I Pathogenic:1

Oct 03, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.049	D
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.2	D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.92		Gain of ubiquitination at K449 (P = 0.0471);Gain of ubiquitination at K449 (P = 0.0471);
MVP		0.96
MPC		0.55
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs118204079; hg19: chr8-19819637;