VCV001207087.15 - ClinVar

NM_178172.6(GPIHBP1):c.368G>A (p.Gly123Glu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_178172.6(GPIHBP1):c.368G>A (p.Gly123Glu)

Variation ID: 1207087 Accession: VCV001207087.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q24.3 8: 143215331 (GRCh38) [ NCBI UCSC ] 8: 144297206 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 21, 2021	Oct 8, 2024	Apr 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_178172.6:c.368G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_835466.2:p.Gly123Glu	missense
NM_001301772.2:c.368G>A	NP_001288701.1:p.Gly123Glu	missense
NC_000008.11:g.143215331G>A
NC_000008.10:g.144297206G>A
NG_034256.1:g.7139G>A

... more HGVS ... less HGVS

Protein change

G123E

Other names

Canonical SPDI

NC_000008.11:143215330:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Exome Aggregation Consortium (ExAC) 0.00047

The Genome Aggregation Database (gnomAD) 0.00049

Trans-Omics for Precision Medicine (TOPMed) 0.00051

The Genome Aggregation Database (gnomAD), exomes 0.00061

Links

dbSNP: rs201685731 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GPIHBP1		-	-	GRCh38 GRCh37	155	220

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 11, 2024	RCV001574958.11
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Sep 18, 2020	RCV002343751.2
Hyperlipoproteinemia, type 1D	Uncertain significance (1)	criteria provided, single submitter	Jun 15, 2022	RCV002468275.2
GPIHBP1-related disorder	Uncertain significance (1)	no assertion criteria provided	Mar 21, 2024	RCV003941025.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jun 15, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hyperlipoproteinemia, type 1D Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV002764281.2 First in ClinVar: Dec 17, 2022 Last updated: May 20, 2023	Observation 1: Clinical Features: Coronary artery atherosclerosis (present) Zygosity: Single Heterozygote Secondary finding: no Observation 2: Clinical Features: Hepatic steatosis (present) , Type 2 diabetes mellitus (present) Zygosity: Single Heterozygote Secondary finding: no
Benign (Dec 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002406760.3 First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024
Benign (Sep 18, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002621421.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 21478160‚ 31153847 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Apr 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001801859.2 First in ClinVar: Aug 21, 2021 Last updated: Oct 08, 2024	Comment: Identified in patients with hypercholesterolemia and hypertriglyceridemia in published literature (PMID: 33303402, 31153847, 36325899); A published functional study suggests that the p.(G123E) variant at no … (more) Identified in patients with hypercholesterolemia and hypertriglyceridemia in published literature (PMID: 33303402, 31153847, 36325899); A published functional study suggests that the p.(G123E) variant at no effect on LPL binding (PMID: 21478160); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31153847, 21478160, 36325899, 33303402) (less)
Uncertain significance (Mar 21, 2024)	no assertion criteria provided Method: clinical testing	GPIHBP1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004761291.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The GPIHBP1 c.368G>A variant is predicted to result in the amino acid substitution p.Gly123Glu. This variant has been reported in an individual with Hypercholesterolemia, although … (more) The GPIHBP1 c.368G>A variant is predicted to result in the amino acid substitution p.Gly123Glu. This variant has been reported in an individual with Hypercholesterolemia, although no further evidence was provided to determine its pathogenicity (Gill et al. 2021. PubMed ID: 33303402. Table S2). This variant has also been reported in a cohort study with lipoprotein metabolism or coronary artery disease (Benes et al. 2019. PubMed ID: 31153847). However, functional study showed that this variant did not affect GPIHBP1 expression (Beigneux et al. 2011. PubMed ID: 21478160). This variant is reported in 0.82% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-144297206-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Identified in patients with hypercholesterolemia and hypertriglyceridemia in published literature (PMID: 33303402, 31153847, 36325899); A published functional study suggests that the p.(G123E) variant at no effect on LPL binding (PMID: 21478160); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31153847, 21478160, 36325899, 33303402)

Comment:

The GPIHBP1 c.368G>A variant is predicted to result in the amino acid substitution p.Gly123Glu. This variant has been reported in an individual with Hypercholesterolemia, although no further evidence was provided to determine its pathogenicity (Gill et al. 2021. PubMed ID: 33303402. Table S2). This variant has also been reported in a cohort study with lipoprotein metabolism or coronary artery disease (Benes et al. 2019. PubMed ID: 31153847). However, functional study showed that this variant did not affect GPIHBP1 expression (Beigneux et al. 2011. PubMed ID: 21478160). This variant is reported in 0.82% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-144297206-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Role of Genetics in Cardiovascular Risk Reduction: Findings From a Single Lipid Clinic and Review of the Literature.	Benes LB	Cardiovascular revascularization medicine : including molecular interventions	2020	PMID: 31153847
Assessing the role of the glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) three-finger domain in binding lipoprotein lipase.	Beigneux AP	The Journal of biological chemistry	2011	PMID: 21478160

Text-mined citations for rs201685731 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_178172.6(GPIHBP1):c.368G>A (p.Gly123Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201685731 ...