ClinVar Genomic variation as it relates to human health
NM_000410.4(HFE):c.670C>T (p.Arg224Trp)
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.670C>T (p.Arg224Trp)
Variation ID: 907725 Accession: VCV000907725.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p22.2 6: 26092738 (GRCh38) [ NCBI UCSC ] 6: 26092966 (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 31, 2020 Mar 4, 2023 Feb 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000410.4:c.670C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000401.1:p.Arg224Trp missense NM_001300749.3:c.670C>T NP_001287678.1:p.Arg224Trp missense NM_001384164.1:c.670C>T NP_001371093.1:p.Arg224Trp missense NM_001406751.1:c.661C>T NP_001393680.1:p.Arg221Trp missense NM_001406752.1:c.406C>T NP_001393681.1:p.Arg136Trp missense NM_139003.3:c.352C>T NP_620572.1:p.Arg118Trp missense NM_139004.3:c.394C>T NP_620573.1:p.Arg132Trp missense NM_139006.3:c.628C>T NP_620575.1:p.Arg210Trp missense NM_139007.3:c.406C>T NP_620576.1:p.Arg136Trp missense NM_139008.3:c.364C>T NP_620577.1:p.Arg122Trp missense NM_139009.3:c.601C>T NP_620578.1:p.Arg201Trp missense NM_139010.3:c.130C>T NP_620579.1:p.Arg44Trp missense NM_139011.3:c.77-381C>T intron variant NC_000006.12:g.26092738C>T NC_000006.11:g.26092966C>T NG_008720.2:g.10458C>T LRG_748:g.10458C>T LRG_748t1:c.670C>T LRG_748p1:p.Arg224Trp - Protein change
- R122W, R210W, R136W, R224W, R44W, R201W, R118W, R132W, R221W
- Other names
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- Canonical SPDI
- NC_000006.12:26092737:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00014
Trans-Omics for Precision Medicine (TOPMed) 0.00016
Exome Aggregation Consortium (ExAC) 0.00019
The Genome Aggregation Database (gnomAD), exomes 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD) 0.00013
- 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
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. |
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HFE | - | - |
GRCh38 GRCh37 |
204 | 295 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2023 | RCV001157774.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 13, 2021 | RCV001776123.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 17, 2021 | RCV002559517.1 |
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
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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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Uncertain significance
(Sep 18, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001319375.1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Sep 17, 2021)
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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: SCV003241716.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine with tryptophan at codon 224 of the HFE protein (p.Arg224Trp). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with tryptophan at codon 224 of the HFE protein (p.Arg224Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs144797937, ExAC 0.07%). This variant has not been reported in the literature in individuals affected with HFE-related conditions. ClinVar contains an entry for this variant (Variation ID: 907725). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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)
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Uncertain significance
(Feb 08, 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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Genome-Nilou Lab
Accession: SCV003801716.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
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Uncertain significance
(May 13, 2021)
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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: SCV002014035.2
First in ClinVar: Nov 12, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in an Italian patient with Parkinson's disease who also harbored the H63D variant; patient reportedly had no altered indices of iron status (Biasiotto et … (more)
Reported in an Italian patient with Parkinson's disease who also harbored the H63D variant; patient reportedly had no altered indices of iron status (Biasiotto et al., 2008); This variant is associated with the following publications: (PMID: 18325820) (less)
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Uncertain significance
(Feb 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hemochromatosis type 1
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807045.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: BP4 supporting
Number of individuals with the variant: 1
Clinical Features:
Poor suck (present) , Cholestasis (present) , Cholestatic liver disease (present) , Maternal fever in pregnancy (present) , Elevated circulating alanine aminotransferase concentration (present) , … (more)
Poor suck (present) , Cholestasis (present) , Cholestatic liver disease (present) , Maternal fever in pregnancy (present) , Elevated circulating alanine aminotransferase concentration (present) , Neonatal sepsis (present) , Maternal hypertension (present) , Jaundice (present) , Birth length less than 3rd percentile (present) , Toxemia of pregnancy (present) , Neonatal hypoglycemia (present) , Prolonged neonatal jaundice (present) , Small for gestational age (present) , Elevated hepatic transaminase (present) , Elevated serum transaminases during infections (present) , Elevated circulating aspartate aminotransferase concentration (present) , Neonatal cholestatic liver disease (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs144797937 ...
HelpRecord last updated Aug 19, 2023
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.