This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_000410.4(HFE):c.502G>C (p.Glu168Gln)
Germline
Classification
Help
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.
(9)
Help
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.
Uncertain significance
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000410.4(HFE):c.502G>C (p.Glu168Gln)
Variation ID: 222651 Accession: VCV000222651.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6p22.2 6: 26091475 (GRCh38) [ NCBI UCSC ] 6: 26091703 (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 Feb 27, 2016 Oct 20, 2024 Jul 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000410.4:c.502G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000401.1:p.Glu168Gln missense NM_001300749.3:c.502G>C NP_001287678.1:p.Glu168Gln missense NM_001384164.1:c.502G>C NP_001371093.1:p.Glu168Gln missense NM_001406751.1:c.502G>C NP_001393680.1:p.Glu168Gln missense NM_001406752.1:c.238G>C NP_001393681.1:p.Glu80Gln missense NM_139003.3:c.340+371G>C intron variant NM_139004.3:c.340+371G>C intron variant NM_139006.3:c.502G>C NP_620575.1:p.Glu168Gln missense NM_139007.3:c.238G>C NP_620576.1:p.Glu80Gln missense NM_139008.3:c.238G>C NP_620577.1:p.Glu80Gln missense NM_139009.3:c.433G>C NP_620578.1:p.Glu145Gln missense NM_139010.3:c.77-1210G>C intron variant NM_139011.3:c.77-1644G>C intron variant NC_000006.12:g.26091475G>C NC_000006.11:g.26091703G>C NG_008720.2:g.9195G>C LRG_748:g.9195G>C LRG_748t1:c.502G>C LRG_748p1:p.Glu168Gln - Protein change
- E168Q, E80Q, E145Q
- Other names
-
p.Glu168Gln
- Canonical SPDI
- NC_000006.12:26091474:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00027
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
Exome Aggregation Consortium (ExAC) 0.00039
The Genome Aggregation Database (gnomAD), exomes 0.00045
The Genome Aggregation Database (gnomAD) 0.00102
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| HFE | - | - |
GRCh38 GRCh37 |
213 | 302 | |
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. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 8, 2023 | RCV000208047.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 24, 2022 | RCV000557367.8 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 18, 2024 | RCV000998548.32 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 22, 2021 | RCV002485360.3 |
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
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hemochromatosis type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001319374.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Jul 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001804916.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 2024 |
Comment:
Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant … (more)
Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant is sufficient to cause disease (PMID: 10953950, 12537660, 12681966, 15477198, 19214108, 19787796); Identified in a patient with hyperferritinemia and analyses suggested this variant was in cis with the p.(His63Asp) variant (PMID: 29084376); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12870733, 12681966, 15477198, 12537660, 12952143, 15025725, 19214108, 19787796, 29590070, 34426522, 10953950, 19759876, 29084376) (less)
|
|
|
Uncertain significance
(Nov 18, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary hemochromatosis
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000263951.2
First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 16, 2018)
|
criteria provided, single submitter
Method: research
|
Hemochromatosis type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Center for Precision Medicine, Vanderbilt University Medical Center
Accession: SCV000889988.1
First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 40
Clinical Features:
cardiac dysrhythmias (present) , pleurisy (present) , congestive heart failure (present) , cardiomyopathy (present) , cardiomegaly (present) , ascites (nonmalignant) (present) , splenomegaly (present) , … (more)
cardiac dysrhythmias (present) , pleurisy (present) , congestive heart failure (present) , cardiomyopathy (present) , cardiomegaly (present) , ascites (nonmalignant) (present) , splenomegaly (present) , cirrhosis of liver without mention of alcohol (present) , type 2 diabetes (present) , osteoporosis (present) , elevated transaminase or LDH (present) , alopecia (present) , absent or infrequent menstruation (present) , hepatomegaly (present) , iron metabolism disorder (present) , hepatic cancer (present) , abnormal glucose (present) , other disorders of testis (present) , testicular hypofunction (present) , erectile dysfunction (present) , other dyschromia (present) , other arthropathies (present) (less)
Method: A phenotype risk score (PheRS) for Hemachromatosis Type 1 was calculated by mapping the disease HPO terms to phecodes, clustered ICD-9 codes that represent phenotypes in the electronic health records. When applied to 21,701 European individuals the PheRS for this disease showed significant association with the rs146519482 variant. Some individuals that are heterozygous for this variant carry phecodes that are consistent with phenotypes associated with this disease. 1 heterozygote for this variant was diagnosed with hemochromatosis and 4/40 heterozygotes underwent liver transplants.
|
|
|
Uncertain significance
(Nov 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease type 1
Familial porphyria cutanea tarda Variegate porphyria Hemochromatosis type 1 Microvascular complications of diabetes, susceptibility to, 7 Transferrin serum level quantitative trait locus 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002776008.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Aug 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary hemochromatosis
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633733.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein (p.Glu168Gln). This variant is present in population databases (rs146519482, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hemochromatosis (PMID: 10953950, 12681966, 15025725, 15477198, 19214108, 19787796). ClinVar contains an entry for this variant (Variation ID: 222651). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hemochromatosis type 1
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV003801493.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
|
|
|
Uncertain significance
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227200.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP4
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001154677.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
HFE: PM2, BP4
Number of individuals with the variant: 2
|
Comment:
Comment:
Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant is sufficient to cause disease (PMID: 10953950, 12537660, 12681966, 15477198, 19214108, 19787796); Identified in a patient with hyperferritinemia and analyses suggested this variant was in cis with the p.(His63Asp) variant (PMID: 29084376); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12870733, 12681966, 15477198, 12537660, 12952143, 15025725, 19214108, 19787796, 29590070, 34426522, 10953950, 19759876, 29084376)
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein (p.Glu168Gln). This variant is present in population databases (rs146519482, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hemochromatosis (PMID: 10953950, 12681966, 15025725, 15477198, 19214108, 19787796). ClinVar contains an entry for this variant (Variation ID: 222651). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
BP4
Comment:
HFE: PM2, BP4
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:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Identified in individuals with hereditary hemochromatosis; however, all reported individuals also harbored other variants in the HFE gene and it remains unclear whether this variant is sufficient to cause disease (PMID: 10953950, 12537660, 12681966, 15477198, 19214108, 19787796); Identified in a patient with hyperferritinemia and analyses suggested this variant was in cis with the p.(His63Asp) variant (PMID: 29084376); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12870733, 12681966, 15477198, 12537660, 12952143, 15025725, 19214108, 19787796, 29590070, 34426522, 10953950, 19759876, 29084376)
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 168 of the HFE protein (p.Glu168Gln). This variant is present in population databases (rs146519482, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hemochromatosis (PMID: 10953950, 12681966, 15025725, 15477198, 19214108, 19787796). ClinVar contains an entry for this variant (Variation ID: 222651). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
BP4
Comment:
HFE: PM2, BP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
| Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. | Bastarache L | Science (New York, N.Y.) | 2018 | PMID: 29590070 |
| Diagnostic value of targeted next-generation sequencing in suspected hemochromatosis patients with a single copy of the HFE p.Cys282Tyr causative allele. | Uguen K | American journal of hematology | 2017 | PMID: 29084376 |
| HFE gene: Structure, function, mutations, and associated iron abnormalities. | Barton JC | Gene | 2015 | PMID: 26456104 |
| Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants. | Aguilar-Martinez P | Haematologica | 2011 | PMID: 21228038 |
| HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high-performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants. | Barton JC | American journal of hematology | 2009 | PMID: 19787796 |
| Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis. | Bittencourt PL | Clinics (Sao Paulo, Brazil) | 2009 | PMID: 19759876 |
| Diagnosis of hepatic iron overload: a family study illustrating pitfalls in diagnosing hemochromatosis. | Schranz M | Diagnostic molecular pathology : the American journal of surgical pathology, part B | 2009 | PMID: 19214108 |
| Screening selected blood donors with biochemical iron overload for hemochromatosis: a regional experience. | De Gobbi M | Haematologica | 2004 | PMID: 15477198 |
| Molecular diagnosis of hereditary hemochromatosis: application of a newly-developed reverse-hybridization assay in the South African population. | Kotze MJ | Clinical genetics | 2004 | PMID: 15025725 |
| HFE gene mutations an Apulian population: allele frequencies. | Pietrapertosa A | European journal of epidemiology | 2003 | PMID: 12952143 |
| Analysis of HFE and TFR2 mutations in selected blood donors with biochemical parameters of iron overload. | De Gobbi M | Haematologica | 2003 | PMID: 12681966 |
| A very rare association of three mutations of the HFE gene for hemochromatosis. | Menardi G | Genetic testing | 2002 | PMID: 12537660 |
| A reverse-hybridization assay for the rapid and simultaneous detection of nine HFE gene mutations. | Oberkanins C | Genetic testing | 2000 | PMID: 10953950 |
| https://www.biorxiv.org/content/10.1101/547471v1.abstract | - | - | - | - |
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Text-mined citations for rs146519482 ...
HelpThese 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 20, 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.