VCV000216425.48 - ClinVar

NM_000410.4(HFE):c.18G>C (p.Arg6Ser)

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.

(11)

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

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.18G>C (p.Arg6Ser)

Variation ID: 216425 Accession: VCV000216425.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.2 6: 26087458 (GRCh38) [ NCBI UCSC ] 6: 26087686 (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	Oct 11, 2015	Nov 24, 2024	Sep 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000410.4:c.18G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000401.1:p.Arg6Ser	missense
NM_001300749.3:c.18G>C	NP_001287678.1:p.Arg6Ser	missense
NM_001384164.1:c.18G>C	NP_001371093.1:p.Arg6Ser	missense
NM_001406751.1:c.18G>C	NP_001393680.1:p.Arg6Ser	missense
NM_001406752.1:c.18G>C	NP_001393681.1:p.Arg6Ser	missense
NM_139003.3:c.18G>C	NP_620572.1:p.Arg6Ser	missense
NM_139004.3:c.18G>C	NP_620573.1:p.Arg6Ser	missense
NM_139006.3:c.18G>C	NP_620575.1:p.Arg6Ser	missense
NM_139007.3:c.18G>C	NP_620576.1:p.Arg6Ser	missense
NM_139008.3:c.18G>C	NP_620577.1:p.Arg6Ser	missense
NM_139009.3:c.18G>C	NP_620578.1:p.Arg6Ser	missense
NM_139010.3:c.18G>C	NP_620579.1:p.Arg6Ser	missense
NM_139011.3:c.18G>C	NP_620580.1:p.Arg6Ser	missense
NR_144383.1:n.1017C>G		non-coding transcript variant
NC_000006.12:g.26087458G>C
NC_000006.11:g.26087686G>C
NG_008720.2:g.5178G>C
LRG_748:g.5178G>C
LRG_748t1:c.18G>C	LRG_748p1:p.Arg6Ser
	Q30201:p.Arg6Ser

... more HGVS ... less HGVS

Protein change

R6S

Other names

NM_000410.3(HFE):c.18G>C(p.Arg6Ser)
NM_001300749.1(HFE):c.18G>C(p.Arg6Ser)
NM_139003.2(HFE):c.18G>C(p.Arg6Ser)
NM_139004.2(HFE):c.18G>C(p.Arg6Ser)
NM_139006.2(HFE):c.18G>C(p.Arg6Ser)
NM_139007.2(HFE):c.18G>C(p.Arg6Ser)
NM_139008.2(HFE):c.18G>C(p.Arg6Ser)
NM_139009.2(HFE):c.18G>C(p.Arg6Ser)
NM_139010.2(HFE):c.18G>C(p.Arg6Ser)
NM_139011.2(HFE):c.18G>C(p.Arg6Ser)

Canonical SPDI

NC_000006.12:26087457:G: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.

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Exome Aggregation Consortium (ExAC) 0.00068

The Genome Aggregation Database (gnomAD), exomes 0.00069

Trans-Omics for Precision Medicine (TOPMed) 0.00070

The Genome Aggregation Database (gnomAD) 0.00072

Links

ClinGen: CA338954 UniProtKB: Q30201#VAR_042506 dbSNP: rs149342416 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	213	302
HFE-AS1	-	-	-	GRCh38	-	77

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.
Hemochromatosis type 1	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Feb 8, 2023	RCV000199898.11
not provided	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Sep 10, 2024	RCV000329080.36
Hereditary hemochromatosis	Uncertain significance (1)	criteria provided, single submitter	Aug 13, 2021	RCV000684802.8
Alzheimer disease type 1 Familial porphyria cutanea tarda Hemochromatosis type 1 Microvascular complications of diabetes, susceptibility to, 7 Transferrin serum level quantitative trait locus 2 Variegate porphyria	Uncertain significance (1)	criteria provided, single submitter	Oct 9, 2021	RCV002485319.3
HFE-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 24, 2024	RCV004737315.1

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 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.
Uncertain significance (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hemochromatosis type 1 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803526.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Hemochromatosis, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: … (more) This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Hemochromatosis, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). (less)
Uncertain significance (Apr 22, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331446.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	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: 1 Sex: mixed
Uncertain significance (Aug 13, 2021)	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: SCV000254531.5 First in ClinVar: Oct 11, 2015 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 28492532‚ 12584229 Comment: This sequence change replaces arginine with serine at codon 6 of the HFE protein (p.Arg6Ser). The arginine residue is highly conserved and there is a … (more) This sequence change replaces arginine with serine at codon 6 of the HFE protein (p.Arg6Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs149342416, ExAC 0.1%). This missense change has been observed in individual(s) with hemochromatosis after receiving a liver transplant from a donor heterozygous for a pathogenic HFE sequence change (PMID: 12584229). ClinVar contains an entry for this variant (Variation ID: 216425). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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)
Uncertain significance (Apr 27, 2017)	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: SCV001317550.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 12584229‚ 15350019 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Oct 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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	Fulgent Genetics, Fulgent Genetics Accession: SCV002775711.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Feb 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Genome-Nilou Lab Accession: SCV003801715.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Uncertain significance (Sep 10, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002013041.4 First in ClinVar: Nov 12, 2021 Last updated: Sep 29, 2024	Comment: Reported in the heterozygous state in an individual who developed evidence of hemochromatosis after liver transplantation for alcoholic cirrhosis; of note, the organ donor was … (more) Reported in the heterozygous state in an individual who developed evidence of hemochromatosis after liver transplantation for alcoholic cirrhosis; of note, the organ donor was known to be heterozygous for the p.(C282Y) variant in the HFE gene, though the precise cause of iron overload in the recipient was not definitively established (PMID: 12584229); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12584229) (less)
Uncertain significance (Aug 01, 2023)	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: SCV001154671.24 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Uncertain significance (Sep 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005412015.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 12584229‚ 15350019 Comment: BP4 Number of individuals with the variant: 2
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970664.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Uncertain significance (Jul 24, 2024)	no assertion criteria provided Method: clinical testing	HFE-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005366151.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The HFE c.18G>C variant is predicted to result in the amino acid substitution p.Arg6Ser. This variant was reported in a heterozygous individual who developed hemochromatosis … (more) The HFE c.18G>C variant is predicted to result in the amino acid substitution p.Arg6Ser. This variant was reported in a heterozygous individual who developed hemochromatosis after receiving a liver transplant by a donor who was a heterozygous carrier for the c.845G>A (p.Cys282Tyr) variant (Wigg et al 2003. PubMed ID: 12584229). Additional studies were not conducted to confirm pathogenicity of the c.18G>C change. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Hemochromatosis, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).

Comment:

This sequence change replaces arginine with serine at codon 6 of the HFE protein (p.Arg6Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs149342416, ExAC 0.1%). This missense change has been observed in individual(s) with hemochromatosis after receiving a liver transplant from a donor heterozygous for a pathogenic HFE sequence change (PMID: 12584229). ClinVar contains an entry for this variant (Variation ID: 216425). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

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, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Reported in the heterozygous state in an individual who developed evidence of hemochromatosis after liver transplantation for alcoholic cirrhosis; of note, the organ donor was known to be heterozygous for the p.(C282Y) variant in the HFE gene, though the precise cause of iron overload in the recipient was not definitively established (PMID: 12584229); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12584229)

Comment:

The HFE c.18G>C variant is predicted to result in the amino acid substitution p.Arg6Ser. This variant was reported in a heterozygous individual who developed hemochromatosis after receiving a liver transplant by a donor who was a heterozygous carrier for the c.845G>A (p.Cys282Tyr) variant (Wigg et al 2003. PubMed ID: 12584229). Additional studies were not conducted to confirm pathogenicity of the c.18G>C change. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Can liver transplantation improve our understanding of the pathophysiology of iron overload?	Brandhagen D	Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society	2004	PMID: 15350019
Heterozygous recipient and donor HFE mutations associated with a hereditary haemochromatosis phenotype after liver transplantation.	Wigg AJ	Gut	2003	PMID: 12584229
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HFE	-	-	-	-

Text-mined citations for rs149342416 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000410.4(HFE):c.18G>C (p.Arg6Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149342416 ...