VCV000129225.59 - ClinVar

NM_000410.4(HFE):c.340+4T>C

Germline

Classification

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.

(12)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000410.4(HFE):c.340+4T>C

Variation ID: 129225 Accession: VCV000129225.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.2 6: 26091108 (GRCh38) [ NCBI UCSC ] 6: 26091336 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 6, 2014	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000410.4:c.340+4T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001300749.3:c.340+4T>C		intron variant
NM_001384164.1:c.340+4T>C		intron variant
NM_001406751.1:c.340+4T>C		intron variant
NM_001406752.1:c.77-206T>C		intron variant
NM_139003.3:c.340+4T>C		intron variant
NM_139004.3:c.340+4T>C		intron variant
NM_139006.3:c.340+4T>C		intron variant
NM_139007.3:c.77-206T>C		intron variant
NM_139008.3:c.77-206T>C		intron variant
NM_139009.3:c.271+4T>C		intron variant
NM_139010.3:c.77-1577T>C		intron variant
NM_139011.3:c.77-2011T>C		intron variant
NC_000006.12:g.26091108T>C
NC_000006.11:g.26091336T>C
NG_008720.2:g.8828T>C
LRG_748:g.8828T>C
LRG_748t1:c.340+4T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000006.12:26091107:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.42672 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.34584

The Genome Aggregation Database (gnomAD) 0.35994

Exome Aggregation Consortium (ExAC) 0.36860

Trans-Omics for Precision Medicine (TOPMed) 0.37348

The Genome Aggregation Database (gnomAD), exomes 0.37541

1000 Genomes Project 30x 0.42536

1000 Genomes Project 0.42672

Links

ClinGen: CA153080 dbSNP: rs2071303 VarSome

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
Gene	OMIM	HI score Help 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.
HFE		-	-	GRCh38 GRCh37	212	301

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.
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Dec 1, 2016	RCV000117221.24
Hereditary hemochromatosis	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000348920.12
Hemochromatosis type 1	Benign (2)	criteria provided, multiple submitters, no conflicts	Aug 10, 2021	RCV001095120.8
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Sep 6, 2018	RCV000860091.28

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304062.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001934137.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Benign (Sep 06, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001944115.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 25262004, 10401000, 26799139, 26501199)
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary hemochromatosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001000013.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Benign (Oct 14, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227125.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HFE Number of individuals with the variant: 34 Sex: mixed
Benign (Dec 01, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712466.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (2) PubMed: 15775762‚ 26799139 Comment: c.340+4T>C in intron 2 of HFE: This variant is not expected to have clinical sig nificance because it has been identified in 37.4% (105403/282154) of … (more) c.340+4T>C in intron 2 of HFE: This variant is not expected to have clinical sig nificance because it has been identified in 37.4% (105403/282154) of total chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs2071303). (less) Number of individuals with the variant: 41
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000461882.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005223299.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Oct 01, 2016)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001154676.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000151393.2 First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929344.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744519.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
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Comment:

c.340+4T>C in intron 2 of HFE: This variant is not expected to have clinical sig nificance because it has been identified in 37.4% (105403/282154) of total chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs2071303).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of novel mutations in hemochromatosis genes by targeted next generation sequencing in Italian patients with unexplained iron overload.	Badar S	American journal of hematology	2016	PMID: 26799139
Is the IVS2+4T>C variant of the HFE gene a splicing mutation or a polymorphism? A study in the Spanish population.	de Lucas AP	Genetics in medicine : official journal of the American College of Medical Genetics	2005	PMID: 15775762
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HFE	-	-	-	-

Text-mined citations for rs2071303 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000410.4(HFE):c.340+4T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2071303 ...