ClinVar Genomic variation as it relates to human health
NM_213653.4(HJV):c.976C>T (p.Arg326Ter)
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_213653.4(HJV):c.976C>T (p.Arg326Ter)
Variation ID: 2366 Accession: VCV000002366.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.1 1: 146018382 (GRCh38) [ NCBI UCSC ] 1: 145416631 (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 Oct 23, 2016 Aug 4, 2024 Jul 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_213653.4:c.976C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_998818.1:p.Arg326Ter nonsense NM_001316767.2:c.298C>T NP_001303696.1:p.Arg100Ter nonsense NM_001379352.1:c.976C>T NP_001366281.1:p.Arg326Ter nonsense NM_145277.5:c.637C>T NP_660320.3:p.Arg213Ter nonsense NM_202004.4:c.298C>T NP_973733.1:p.Arg100Ter nonsense NM_213652.4:c.298C>T NP_998817.1:p.Arg100Ter nonsense NC_000001.11:g.146018382G>A NC_000001.10:g.145416631C>T NG_011568.1:g.8441C>T - Protein change
- R326*, R213*, R100*
- Other names
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- Canonical SPDI
- NC_000001.11:146018381: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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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HJV | - | - |
GRCh38 GRCh37 |
385 | 572 |
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
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 22, 2024 | RCV000002463.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 18, 2023 | RCV001216451.6 |
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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Pathogenic
(Dec 18, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001388248.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg326*) in the HJV gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg326*) in the HJV gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the HJV protein. This variant is present in population databases (rs74315324, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with juvenile hemochromatosis (PMID: 14647275). ClinVar contains an entry for this variant (Variation ID: 2366). This variant disrupts a region of the HJV protein in which other variant(s) (p.Gly336*) have been determined to be pathogenic (PMID: 30195625; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hemochromatosis type 2A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003845121.2
First in ClinVar: Mar 26, 2023 Last updated: Mar 30, 2024 |
Comment:
Variant summary: HJV c.976C>T (p.Arg326X) results in a premature termination codon located in the last exon, therefore not expected to cause nonsense mediated decay (NMD), … (more)
Variant summary: HJV c.976C>T (p.Arg326X) results in a premature termination codon located in the last exon, therefore not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a large part of the 426 amino acid long protein (InterPro). Truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 1.2e-05 in 251340 control chromosomes (gnomAD). c.976C>T has been reported in the literature in compound heterozygous individuals affected with Hemochromatosis Type 2A (Papanikolaou_2003, Wallace_2004). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hemochromatosis type 2A
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV000915352.2
First in ClinVar: May 27, 2019 Last updated: Aug 04, 2024 |
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Pathogenic
(Jan 01, 2004)
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no assertion criteria provided
Method: literature only
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HEMOCHROMATOSIS, TYPE 2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022621.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
For discussion of the arg326-to-ter (R326X) mutation in the HJV gene that was found in compound heterozygous state in patients with juvenile hemochromatosis (HFE2A; 602390) … (more)
For discussion of the arg326-to-ter (R326X) mutation in the HJV gene that was found in compound heterozygous state in patients with juvenile hemochromatosis (HFE2A; 602390) by Papanikolaou et al. (2004), see 608374.0001. (less)
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Likely pathogenic
(Aug 25, 2021)
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no assertion criteria provided
Method: clinical testing
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Hemochromatosis type 2A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002085768.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Juvenile Hemochromatosis: A Case Report and Review of the Literature. | Takami A | Pharmaceuticals (Basel, Switzerland) | 2020 | PMID: 32824233 |
Adult onset hereditary hemochromatosis is associated with a novel recurrent Hemojuvelin (HJV) gene mutation in north Indians. | Dhillon BK | Blood cells, molecules & diseases | 2018 | PMID: 30195625 |
Next-generation sequencing: Application of a novel platform to analyze atypical iron disorders. | McDonald CJ | Journal of hepatology | 2015 | PMID: 26151776 |
Hemojuvelin (HJV)-associated hemochromatosis: analysis of HJV and HFE mutations and iron overload in three families. | Wallace DF | Haematologica | 2005 | PMID: 15710580 |
Prevalence of the G320V mutation of the HJV gene, associated with juvenile hemochromatosis, in Greece. | Pissia M | Haematologica | 2004 | PMID: 15194541 |
Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. | Papanikolaou G | Nature genetics | 2004 | PMID: 14647275 |
Text-mined citations for rs74315324 ...
HelpRecord last updated Sep 29, 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.