ClinVar Genomic variation as it relates to human health
NM_000410.4(HFE):c.848A>C (p.Gln283Pro)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000410.4(HFE):c.848A>C (p.Gln283Pro)
Variation ID: 19 Accession: VCV000000019.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p22.2 6: 26092916 (GRCh38) [ NCBI UCSC ] 6: 26093144 (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 May 5, 2018 Apr 15, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000410.4:c.848A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000401.1:p.Gln283Pro missense NM_001300749.3:c.848A>C NP_001287678.1:p.Gln283Pro missense NM_001384164.1:c.848A>C NP_001371093.1:p.Gln283Pro missense NM_001406751.1:c.839A>C NP_001393680.1:p.Gln280Pro missense NM_001406752.1:c.584A>C NP_001393681.1:p.Gln195Pro missense NM_139003.3:c.530A>C NP_620572.1:p.Gln177Pro missense NM_139004.3:c.572A>C NP_620573.1:p.Gln191Pro missense NM_139006.3:c.806A>C NP_620575.1:p.Gln269Pro missense NM_139007.3:c.584A>C NP_620576.1:p.Gln195Pro missense NM_139008.3:c.542A>C NP_620577.1:p.Gln181Pro missense NM_139009.3:c.779A>C NP_620578.1:p.Gln260Pro missense NM_139010.3:c.308A>C NP_620579.1:p.Gln103Pro missense NM_139011.3:c.77-203A>C intron variant NC_000006.12:g.26092916A>C NC_000006.11:g.26093144A>C NG_008720.2:g.10636A>C LRG_748:g.10636A>C LRG_748t1:c.848A>C LRG_748p1:p.Gln283Pro Q30201:p.Gln283Pro - Protein change
- Q283P, Q191P, Q269P, Q103P, Q177P, Q195P, Q260P, Q181P, Q280P
- Other names
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- Canonical SPDI
- NC_000006.12:26092915:A: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
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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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HFE | - | - |
GRCh38 GRCh37 |
205 | 293 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Jul 3, 2023 | RCV000000036.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2022 | RCV001050090.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2024 | RCV003884332.2 |
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
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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
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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
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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 pathogenic
(Jul 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hemochromatosis type 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004028688.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: HFE c.848A>C (p.Gln283Pro) results in a non-conservative amino acid change located in the Immunoglobulin C1-set domain (IPR003597) of the encoded protein sequence. Four … (more)
Variant summary: HFE c.848A>C (p.Gln283Pro) results in a non-conservative amino acid change located in the Immunoglobulin C1-set domain (IPR003597) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251294 control chromosomes. c.848A>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Hemochromatosis Type 1 (example, LeGac_2003, van Gammeren_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a highly reduced capacity of mutant HFE to reduce transferrin-mediated iron uptake and abolished ability to form complexes with beta2 microglobulin and Transferrin 1 (Ka_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15965644, 12737937, 33791166, 25850353). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Sep 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary hemochromatosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001214178.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects HFE function (PMID: 15965644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HFE protein function. ClinVar contains an entry for this variant (Variation ID: 19). This missense change has been observed in individual(s) with hereditary hemochromatosis (PMID: 12737937, 25850353). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 283 of the HFE protein (p.Gln283Pro). (less)
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Likely pathogenic
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004702708.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
HFE: PM3:Strong, PM2, PS3:Supporting, BP4
Number of individuals with the variant: 1
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Pathogenic
(Sep 01, 2005)
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no assertion criteria provided
Method: literature only
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HEMOCHROMATOSIS, TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020179.4
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2018 |
Comment on evidence:
In affected members of a French family with hemochromatosis (235200), Le Gac et al. (2003) identified compound heterozygosity for 2 mutations in the HFE gene: … (more)
In affected members of a French family with hemochromatosis (235200), Le Gac et al. (2003) identified compound heterozygosity for 2 mutations in the HFE gene: an 848A-C transversion in exon 4, resulting in a gln283-to-pro (Q283P) substitution within the alpha-3 domain, and a C282Y (613609.0001) substitution. Molecular modeling studies predicted a destabilizing effect for the Q283P substitution on the tertiary structure of the protein. By performing immunoprecipitation studies in HeLa cells, Ka et al. (2005) found that the Q283P mutation prevented the normal interaction between HFE protein and beta-2-microglobulin (B2M; 109700) and between HFE protein and transferrin receptor (TFRC; 190010). Further studies showed that the Q283P mutation decreased the capacity of HFE to reduce transferrin-mediated iron uptake. Ka et al. (2005) noted that the Q283P mutation is adjacent to the disulfide bridge formed by cys225 and cys282, and concluded that the Q283P protein is retained in the endoplasmic reticulum and middle Golgi compartments, similar to the C282Y mutant protein. The results indicated that the Q283P mutation leads to structural and functional consequences similar to those described for the more common C282Y mutation. (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
HelpTitle | Author | Journal | Year | Link |
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Impact of HFE gene variants on iron overload, overall survival and leukemia-free survival in myelodysplastic syndromes. | Schneeweiss-Gleixner M | American journal of cancer research | 2021 | PMID: 33791166 |
Compound heterozygous C282Y/Q283P and Q283P/H63D mutations in haemochromatosis. | van Gammeren A | British journal of haematology | 2015 | PMID: 25850353 |
The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein. | Ka C | Human genetics | 2005 | PMID: 15965644 |
Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect. | Le Gac G | Blood cells, molecules & diseases | 2003 | PMID: 12737937 |
Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. | Lebrón JA | Cell | 1998 | PMID: 9546397 |
Text-mined citations for rs111033563 ...
HelpRecord last updated Apr 15, 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.