dbSNP rs587777638: GPIHBP1:p.Cys65Tyr (chr8-143215025-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_178172.6(GPIHBP1):c.194G>A(p.Cys65Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,427,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GPIHBP1
NM_178172.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.512

Variant links:

Genes affected

GPIHBP1 (HGNC:24945): (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1) This gene encodes a capillary endothelial cell protein that facilitates the lipolytic processing of triglyceride-rich lipoproteins. The encoded protein is a glycosylphosphatidylinositol-anchored protein that is a member of the lymphocyte antigen 6 (Ly6) family. This protein plays a major role in transporting lipoprotein lipase (LPL) from the subendothelial spaces to the capillary lumen. Mutations in this gene are the cause of hyperlipoproteinemia, type 1D. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

GPIHBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 8-143215025-G-A is Pathogenic according to our data. Variant chr8-143215025-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 144020.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPIHBP1	NM_178172.6 link	c.194G>A	p.Cys65Tyr	missense_variant	Exon 3 of 4	ENST00000622500.2	NP_835466.2	Q8IV16
GPIHBP1	NM_001301772.2 link	c.194G>A	p.Cys65Tyr	missense_variant	Exon 3 of 5		NP_001288701.1	Q8IV16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPIHBP1	ENST00000622500.2 link	c.194G>A	p.Cys65Tyr	missense_variant	Exon 3 of 4	1	NM_178172.6	ENSP00000480053.1		Q8IV16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000102

AC:

AN:

196078

Hom.:

AF XY:

0.00000940

AC XY:

AN XY:

106430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000374

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1427042

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.13e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type I

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.194G>A (p.Cys65Tyr) variant in the GPIHBP1 gene has been reported previously in homozygous state in patients affected with severe chylomicronemia. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1- p.Cys65Tyr reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL) (Franssen, Remco et al., 2010). The variant is located in a mutational hot spot. A different missense change p.Cys65Ser has been reported as pathogenic (Holmes RS, Cox LA., 2012). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic. The amino acid Cysteine at position 65 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Cys65Tyr in GPIHBP1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Hyperlipoproteinemia, type 1D

Pathogenic:1

Aug 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Benign

0.96

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.66

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.96

PrimateAI

Uncertain

0.53

Sift4G

Pathogenic

0.0

Vest4

0.89

MutPred

0.93

Gain of sheet (P = 0.0043);

MVP

0.93

ClinPred

0.55

GERP RS

3.0

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over