ClinVar Genomic variation as it relates to human health
NM_000410.4(HFE):c.829G>A (p.Glu277Lys)
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.
Uncertain significance(2); Benign(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000410.4(HFE):c.829G>A (p.Glu277Lys)
Variation ID: 356196 Accession: VCV000356196.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p22.2 6: 26092897 (GRCh38) [ NCBI UCSC ] 6: 26093125 (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 Dec 6, 2016 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000410.4:c.829G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000401.1:p.Glu277Lys missense NM_001300749.3:c.829G>A NP_001287678.1:p.Glu277Lys missense NM_001384164.1:c.829G>A NP_001371093.1:p.Glu277Lys missense NM_001406751.1:c.820G>A NP_001393680.1:p.Glu274Lys missense NM_001406752.1:c.565G>A NP_001393681.1:p.Glu189Lys missense NM_139003.3:c.511G>A NP_620572.1:p.Glu171Lys missense NM_139004.3:c.553G>A NP_620573.1:p.Glu185Lys missense NM_139006.3:c.787G>A NP_620575.1:p.Glu263Lys missense NM_139007.3:c.565G>A NP_620576.1:p.Glu189Lys missense NM_139008.3:c.523G>A NP_620577.1:p.Glu175Lys missense NM_139009.3:c.760G>A NP_620578.1:p.Glu254Lys missense NM_139010.3:c.289G>A NP_620579.1:p.Glu97Lys missense NM_139011.3:c.77-222G>A intron variant NC_000006.12:g.26092897G>A NC_000006.11:g.26093125G>A NG_008720.2:g.10617G>A LRG_748:g.10617G>A LRG_748t1:c.829G>A LRG_748p1:p.Glu277Lys Q30201:p.Glu277Lys - Protein change
- E277K, E189K, E171K, E185K, E254K, E175K, E263K, E97K, E274K
- Other names
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- Canonical SPDI
- NC_000006.12:26092896:G:A
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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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0.00180 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
Trans-Omics for Precision Medicine (TOPMed) 0.00079
The Genome Aggregation Database (gnomAD) 0.00081
1000 Genomes Project 0.00180
1000 Genomes Project 30x 0.00203
The Genome Aggregation Database (gnomAD), exomes 0.00356
Exome Aggregation Consortium (ExAC) 0.00390
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 | ||
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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
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. |
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HFE | - | - |
GRCh38 GRCh37 |
205 | 293 |
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. |
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Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001084109.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 3, 2016 | RCV000473336.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000727614.13 |
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
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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Uncertain significance
(Oct 10, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000854872.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Uncertain significance
(Aug 03, 2016)
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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: SCV000461886.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The HFE c.829G>A (p.Glu277Lys) variant is a missense variant that has been reported in at least one study, in which it was found in a … (more)
The HFE c.829G>A (p.Glu277Lys) variant is a missense variant that has been reported in at least one study, in which it was found in a compound heterozygous state with a second missense variant in one Portuguese individual with suspected hereditary hemochromatosis (Mendes et al. 2009). Family studies showed that the individual's brother had the same genotype and high serum ferritin levels. Functional studies by Silva et al. (2012) suggest that the p.Glu277Lys variant affects splicing, protein cell surface presentation and protein processing. The p.Glu277Lys variant was absent from 50 controls (Bradbury et al. 2000) and is reported at a frequency of 0.02459 in the South Asian population of the Exome Aggregation Consortium. This allele frequency is high but is consistent with the disease prevalence, reduced penetrance and mild phenotype. The evidence for this variant is limited. The p.Glu277Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for hereditary hemochromatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Benign
(May 18, 2020)
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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: SCV001829973.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 27153395, 27884173, 10612845, 22624560, 18762941)
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Likely benign
(Jan 31, 2024)
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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: SCV000557781.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
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Benign
(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: SCV004700295.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
HFE: BP4, BS1, BS2
Number of individuals with the variant: 2
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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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The functional significance of E277K and V295A HFE mutations. | Silva B | British journal of haematology | 2012 | PMID: 22624560 |
Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes. | Mendes AI | Annals of hematology | 2009 | PMID: 18762941 |
Two novel polymorphisms (E277K and V212V) in the haemochromatosis gene HFE. | Bradbury R | Human mutation | 2000 | PMID: 10612845 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HFE | - | - | - | - |
Text-mined citations for rs140080192 ...
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.