rs587777638

Variant names:

• chr8-143215025-G-A
• rs587777638
• NM_178172.6:c.194G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-143215025-G-A
• chr8-143215025-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_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 (★). ClinVar reports functional evidence for this variant: "SCV005060868: 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C65S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPIHBP1 NM_178172.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.512
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• hyperlipoproteinemia, type 1D

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005060868: 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).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_178172.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-143215025-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 144014.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 VariationId is 144020.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178172.6. 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
	GPIHBP1	NM_178172.6	MANE Select	c.194G>A	p.Cys65Tyr	missense	Exon 3 of 4	NP_835466.2	Q8IV16
	GPIHBP1	NM_001301772.2		c.194G>A	p.Cys65Tyr	missense	Exon 3 of 5	NP_001288701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPIHBP1	ENST00000622500.2	TSL:1 MANE Select	c.194G>A	p.Cys65Tyr	missense	Exon 3 of 4	ENSP00000480053.1	Q8IV16
	GPIHBP1	ENST00000852007.1		c.239G>A	p.Cys80Tyr	missense	Exon 4 of 5	ENSP00000522066.1
	GPIHBP1	ENST00000852008.1		c.194G>A	p.Cys65Tyr	missense	Exon 3 of 4	ENSP00000522067.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 196078 AF XY: 0.00000940

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1427042 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 707554

African (AFR) AF: 0.00 AC: 0 AN: 32226

American (AMR) AF: 0.00 AC: 0 AN: 39578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 36892

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095148

Other (OTH) AF: 0.00 AC: 0 AN: 59032

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperlipoproteinemia, type 1D (1)
1	-	-	Hyperlipoproteinemia, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.66	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
PhyloP100		0.51
PrimateAI	Uncertain	0.53	T
Sift4G	Pathogenic	0.0	D
Vest4		0.89
MutPred		0.93		Gain of sheet (P = 0.0043)
MVP		0.93
ClinPred		0.55	D
GERP RS		3.0
gMVP		0.99
Mutation Taster		=16/84	disease causing (ClinVar)

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: rs587777638; hg19: chr8-144296900; COSMIC: COSV58209300;