ClinVar Genomic variation as it relates to human health
NM_178172.6(GPIHBP1):c.523G>C (p.Gly175Arg)
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.
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.
Likely pathogenic(1); Uncertain significance(7); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_178172.6(GPIHBP1):c.523G>C (p.Gly175Arg)
Variation ID: 144016 Accession: VCV000144016.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.3 8: 143215486 (GRCh38) [ NCBI UCSC ] 8: 144297361 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 25, 2014 May 1, 2024 Mar 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_178172.6:c.523G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_835466.2:p.Gly175Arg missense NM_001301772.2:c.375+148G>C intron variant NC_000008.11:g.143215486G>C NC_000008.10:g.144297361G>C NG_034256.1:g.7294G>C - Protein change
- G175R
- Other names
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GPIHBP1, GLY175ARG (rs145844329)
- Canonical SPDI
- NC_000008.11:143215485:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00220 (C)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00208
Trans-Omics for Precision Medicine (TOPMed) 0.00211
1000 Genomes Project 0.00220
1000 Genomes Project 30x 0.00250
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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| HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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| GPIHBP1 | - | - |
GRCh38 GRCh37 |
155 | 220 | |
Conditions - Germline
| Condition
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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. |
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| Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Mar 29, 2024 | RCV000133525.23 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 8, 2024 | RCV000948350.19 | |
| Likely benign (1) |
criteria provided, single submitter
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Dec 6, 2022 | RCV003162597.9 | |
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GPIHBP1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Nov 14, 2022 | RCV003415969.5 |
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. |
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Likely benign
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001094554.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Uncertain significance
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type 1D
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807493.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Jun 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type ID
Affected status: yes
Allele origin:
germline
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Hadassah Hebrew University Medical Center
Accession: SCV001430594.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type 1D
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440309.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Uncertain significance
(Jan 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type 1D
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984687.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Uncertain significance
(May 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002600948.2
First in ClinVar: Nov 19, 2022 Last updated: Mar 04, 2023 |
Comment:
In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change … (more)
In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 34426522, 31589614, 33303402, 21816778, 31785789) (less)
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Uncertain significance
(Jan 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipoproteinemia, type 1D
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV004046579.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Observation 1:
Clinical Features:
Hyperlipidemia (present) , Type 2 diabetes mellitus (present)
Secondary finding: no
Observation 2:
Clinical Features:
Diabetes mellitus (present)
Secondary finding: no
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Uncertain significance
(Nov 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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GPIHBP1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108591.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GPIHBP1 c.523G>C variant is predicted to result in the amino acid substitution p.Gly175Arg. This variant has been reported in the heterozygous and homozygous states … (more)
The GPIHBP1 c.523G>C variant is predicted to result in the amino acid substitution p.Gly175Arg. This variant has been reported in the heterozygous and homozygous states in individuals with pancreatitis, diabetes and hyperchylomicronemia (Charrière et al. 2011. PubMed ID: 21816778; Laurijssen et al. 2022. PubMed ID: 35770288). This variant has also been reported in the heterozygous state in individuals with hypertriglyceridemia, hyperlipidemia and Hyperlipoproteinemia (Chyzhyk et al. 2019. PubMed ID: 30352774; Gill et al. 2020. PubMed ID: 33303402, Table S2; Mor-Shaked et al. 2020. PubMed ID: 33223529). Functional studies showed this variant resulted in reducing the expression of GPIHBP1 at the cell surface; however, the significance of this finding is unclear (Charrière et al. 2011. PubMed ID: 21816778). In ClinVar, this variant has conflicting interpretations of likely benign, uncertain significance, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/144016/). This variant is reported in 0.55% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-144297361-G-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Dec 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003903929.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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)
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Uncertain significance
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224221.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM3_supporting, PS3_supporting
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2011)
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no assertion criteria provided
Method: literature only
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HYPERLIPOPROTEINEMIA, TYPE ID
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000188600.3
First in ClinVar: Aug 25, 2014 Last updated: Jan 15, 2022 |
Comment on evidence:
In a 35-year-old man with severe chylomicronemia (615947), Charriere et al. (2011) identified homozygosity for a G-to-C substitution in exon 4 of the GPIHBP1 gene, … (more)
In a 35-year-old man with severe chylomicronemia (615947), Charriere et al. (2011) identified homozygosity for a G-to-C substitution in exon 4 of the GPIHBP1 gene, resulting in a gly175-to-arg (G175R) substitution in the C-terminal domain of the protein. The mutation altered the transfer of GPIHBP1 at the cell surface and reduced the ability of GPIHBP1 to bind LPL to just above 50% of wildtype levels. The mutation was not found in 220 normolipemic controls. Hamosh (2014) noted that the G175R mutation (rs145844329), was seen with a frequency of 27 in 12,970 alleles in the Exome Variant Server database but was not seen in homozygosity. (less)
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Likely pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Hyperlipoproteinemia, type ID
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142393.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_178172.3:c.523G>C in the GPIHBP1 gene has an allele frequency of 0.005 in African subpopulation in the gnomAD database. The GPIHBP1 c.523G>C (p.Gly175Arg) variant has been … (more)
NM_178172.3:c.523G>C in the GPIHBP1 gene has an allele frequency of 0.005 in African subpopulation in the gnomAD database. The GPIHBP1 c.523G>C (p.Gly175Arg) variant has been detected one individual affected with hyperchylomicronemia in homozygous state (PMID: 21816778). Functional study revealed that G175R variant reduced the expression of GPIHBP1 at the cell surface of CHOpgsA-745 cells (PMID: 21816778). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3; PS3; PP4. (less)
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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. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010-2020: a cross-sectional study. | Rodriguez FH | Lipids in health and disease | 2023 | PMID: 36978188 |
| Pancreatitis, pregestational diabetes and hyperchylomicronia in a pregnant woman with COVID-19. | Laurijssen S | Acta gastro-enterologica Belgica | 2022 | PMID: 35770288 |
| Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia. | Gill PK | Journal of clinical lipidology | 2021 | PMID: 33303402 |
| Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child. | Mor-Shaked H | European journal of human genetics : EJHG | 2021 | PMID: 33223529 |
| Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders. | Turner TN | American journal of human genetics | 2019 | PMID: 31785789 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence. | Chyzhyk V | Journal of clinical lipidology | 2019 | PMID: 30352774 |
| GPIHBP1 and Plasma Triglyceride Metabolism. | Fong LG | Trends in endocrinology and metabolism: TEM | 2016 | PMID: 27185325 |
| GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia. | Charrière S | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21816778 |
| Hamosh, A. Personal Communication. 2014. Baltimore, Md. | - | - | - | - |
Text-mined citations for rs145844329 ...
HelpRecord last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.