ClinVar Genomic variation as it relates to human health
NM_000410.4(HFE):c.1006+1G>A
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.1006+1G>A
Variation ID: 1065637 Accession: VCV001065637.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p22.2 6: 26093233 (GRCh38) [ NCBI UCSC ] 6: 26093461 (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 10, 2021 Feb 14, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000410.4:c.1006+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001300749.3:c.1006+1G>A splice donor NM_001384164.1:c.1006+1G>A splice donor NM_001406751.1:c.997+1G>A splice donor NM_001406752.1:c.742+1G>A splice donor NM_139003.3:c.688+1G>A splice donor NM_139004.3:c.730+1G>A splice donor NM_139006.3:c.964+1G>A splice donor NM_139007.3:c.742+1G>A splice donor NM_139008.3:c.700+1G>A splice donor NM_139009.3:c.937+1G>A splice donor NM_139010.3:c.466+1G>A splice donor NM_139011.3:c.190+1G>A splice donor NC_000006.12:g.26093233G>A NC_000006.11:g.26093461G>A NG_008720.2:g.10953G>A LRG_748:g.10953G>A LRG_748t1:c.1006+1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000006.12:26093232: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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
- 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 | ||
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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 |
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 pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2023 | RCV001376186.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV002493912.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2023 | RCV002550228.3 | |
Likely pathogenic (1) |
criteria provided, multiple submitters, no conflicts
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Feb 3, 2023 | RCV003145645.3 |
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. |
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Likely pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hemochromatosis type 1
Affected status: no
Allele origin:
germline
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School of Computer Science, University of Waterloo
Accession: SCV001573238.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
Evidence categories PVS1 and PM2 in ACMG guidelines. This is a splice donor variant in gene HFE that may disrupt mRNA splicing and result in … (more)
Evidence categories PVS1 and PM2 in ACMG guidelines. This is a splice donor variant in gene HFE that may disrupt mRNA splicing and result in an absent or disrupted protein product. (less)
Number of individuals with the variant: 15
Sex: mixed
Ethnicity/Population group: Vietnamese
Geographic origin: Vietnam
Testing laboratory: Gene Solutions, Vietnam
Date variant was reported to submitter: 2021-05-06
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Likely pathogenic
(Feb 17, 2022)
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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: SCV002103476.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: HFE c.1006+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: HFE c.1006+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.4e-05 in 251332 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HFE causing Hemochromatosis Type 1 (6.4e-05 vs 0.046), allowing no conclusion about variant significance. c.1006+1G>A has been reported in the literature in individuals affected with Hemochromatosis Type 1 (Hamdi-Roze_2016). However, a case-control study showed that this variant was not associated with serum ferritin or transferrin saturation (Steiner_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS. (less)
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Pathogenic
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002798294.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(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: SCV003802012.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
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Likely pathogenic
(Feb 03, 2023)
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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: SCV004023621.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing; RNA analysis has demonstrated skipping of exon 5 (Steiner et al., 2002); Common variant among … (more)
Canonical splice site variant expected to result in aberrant splicing; RNA analysis has demonstrated skipping of exon 5 (Steiner et al., 2002); Common variant among the Kinh Vietnamese (KHV) people (Le et al., 2019); This variant is associated with the following publications: (PMID: 25525159, 20008199, 17661915, 15965644, 31180159, 16570681, 12737949, 17240320, 26456104, 23577916, 16234038, 16132052, 11875012, 15182337, 16443912, 27518069) (less)
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Likely pathogenic
(Apr 19, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003834236.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 30, 2023)
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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: SCV003523426.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 5 of the HFE gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects a donor splice site in intron 5 of the HFE gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs573745685, gnomAD 0.08%). Disruption of this splice site has been observed in individuals with hereditary hemochromatosis (PMID: 11875012, 17240320, 27518069). ClinVar contains an entry for this variant (Variation ID: 1065637). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 11875012). For these reasons, this variant has been classified as Pathogenic. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hemochromatosis type 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV004100678.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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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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HFE-Related Hemochromatosis. | Adam MP | - | 2024 | PMID: 20301613 |
Rare HFE variants are the most frequent cause of hemochromatosis in non-c282y homozygous patients with hemochromatosis. | Hamdi-Rozé H | American journal of hematology | 2016 | PMID: 27518069 |
HFE gene: Structure, function, mutations, and associated iron abnormalities. | Barton JC | Gene | 2015 | PMID: 26456104 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs573745685 ...
HelpRecord last updated Apr 06, 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.