VCV000000010.114 - ClinVar

NM_000410.4(HFE):c.187C>G (p.His63Asp)

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.

(51)

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.

Pathogenic/Likely pathogenic/Pathogenic, low penetrance; other

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.187C>G (p.His63Asp)

Variation ID: 10 Accession: VCV000000010.114

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p22.2 6: 26090951 (GRCh38) [ NCBI UCSC ] 6: 26091179 (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	Sep 29, 2015	Oct 20, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000410.4:c.187C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000401.1:p.His63Asp	missense
NM_001300749.3:c.187C>G	NP_001287678.1:p.His63Asp	missense
NM_001384164.1:c.187C>G	NP_001371093.1:p.His63Asp	missense
NM_001406751.1:c.187C>G	NP_001393680.1:p.His63Asp	missense
NM_139003.3:c.187C>G	NP_620572.1:p.His63Asp	missense
NM_139004.3:c.187C>G	NP_620573.1:p.His63Asp	missense
NM_139006.3:c.187C>G	NP_620575.1:p.His63Asp	missense
NM_139007.3:c.77-363C>G		intron variant
NM_139008.3:c.77-363C>G		intron variant
NM_139009.3:c.118C>G	NP_620578.1:p.His40Asp	missense
NM_139010.3:c.77-1734C>G		intron variant
NM_139011.3:c.77-2168C>G		intron variant
NR_144383.1:n.84G>C		non-coding transcript variant
NC_000006.12:g.26090951C>G
NC_000006.11:g.26091179C>G
NG_008720.2:g.8671C>G
LRG_748:g.8671C>G
LRG_748t1:c.187C>G	LRG_748p1:p.His63Asp
	Q30201:p.His63Asp

... more HGVS ... less HGVS

Protein change

H63D, H40D

Other names

Canonical SPDI

NC_000006.12:26090950:C:G

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

Unknown function

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.

0.07308 (G)

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

1000 Genomes Project 0.07308

1000 Genomes Project 30x 0.07386

Trans-Omics for Precision Medicine (TOPMed) 0.10048

The Genome Aggregation Database (gnomAD) 0.10170

Exome Aggregation Consortium (ExAC) 0.10660

The Genome Aggregation Database (gnomAD), exomes 0.10924

Links

ClinGen: CA113797 Genetic Testing Registry (GTR): GTR000019607 Genetic Testing Registry (GTR): GTR000021464 Genetic Testing Registry (GTR): GTR000021488 Genetic Testing Registry (GTR): GTR000159973 Genetic Testing Registry (GTR): GTR000219921 Genetic Testing Registry (GTR): GTR000264968 Genetic Testing Registry (GTR): GTR000271417 Genetic Testing Registry (GTR): GTR000321635 Genetic Testing Registry (GTR): GTR000323017 Genetic Testing Registry (GTR): GTR000500300 Genetic Testing Registry (GTR): GTR000500796 Genetic Testing Registry (GTR): GTR000558915 Genetic Testing Registry (GTR): GTR000560787 Genetic Testing Registry (GTR): GTR000568258 Genetic Testing Registry (GTR): GTR000576400 Genetic Testing Registry (GTR): GTR000607867 UniProtKB: Q30201#VAR_004396 OMIM: 613609.0002 dbSNP: rs1799945 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	Pathogenic/Likely pathogenic (28)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000000026.69
not provided	Pathogenic; other (13)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000175607.56
Hereditary hemochromatosis	Pathogenic, low penetrance (2)	criteria provided, single submitter	Jan 31, 2024	RCV000394716.27
Alzheimer disease Familial porphyria cutanea tarda Hemochromatosis type 1 Microvascular complications of diabetes, susceptibility to, 7 Transferrin serum level quantitative trait locus 2 Variegate porphyria	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763144.10
not specified	no classifications from unflagged records (2)	no classifications from unflagged records	Nov 29, 2022	RCV000844708.17
Cystic fibrosis	risk factor (1)	no assertion criteria provided	Apr 1, 2019	RCV000991133.10
Bronze diabetes	not provided (1)	no classification provided	-	RCV001248831.11
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Mar 25, 2021	RCV001731265.11
Variegate porphyria	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2020	RCV002272003.9
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 10, 2021	RCV004584302.1

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.
Pathogenic (Nov 26, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Hereditary hemochromatosis Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000206973.2 First in ClinVar: Feb 06, 2015 Last updated: Feb 26, 2016	Number of individuals with the variant: 9
Pathogenic (Jan 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000223933.2 First in ClinVar: Oct 05, 2015 Last updated: Oct 23, 2016	Comment: The c.187C>G (p.His63Asp) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Compound heterozygotes for p.Cys282Tyr … (more) The c.187C>G (p.His63Asp) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Compound heterozygotes for p.Cys282Tyr and p.His63Asp are common in the Caucasian population, and together with homozygotes for the p.Cys282Tyr, account for 87% of individuals of European origin with HFE-HH. However, it is important to note that only ~ 0.5%-2.0% of compound heterozygous individuals develop clinical evidence of the disease due to incomplete penetrance (GeneReviews: Seckington et al., 2015; Ramrakhiani and Bacon, 1998; Morrison et al., 2003). In summary, this variant c.187C>G, (p.His63Asp) meets our criteria for Pathogenic. (less)
Pathogenic (Sep 14, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000693430.2 First in ClinVar: Apr 19, 2018 Last updated: May 05, 2018
other (Jun 26, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227124.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 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: 348 Sex: mixed
Pathogenic (Oct 31, 2018)	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: SCV000893709.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137061.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020
Pathogenic (Dec 26, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194094.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (6) PubMed: 9462220‚ 11904676‚ 11358905‚ 19159930‚ 19554541‚ 14673107 Comment: NM_000410.3(HFE):c.187C>G(H63D) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. H63D is only associated with clinical hemochromatosis in the presence of some other … (more) NM_000410.3(HFE):c.187C>G(H63D) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. H63D is only associated with clinical hemochromatosis in the presence of some other genetic variant or condition that affects iron metabolism such as the C282Y variant or liver disease. Sources cited for classification include the following: PMID 9462220, 11904676, 11358905, 19159930, 19554541 and 14673107. Classification of NM_000410.3(HFE):c.187C>G(H63D) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Sep 25, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368348.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4,PP4.
Pathogenic (Feb 26, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001519563.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (10) PubMed: 31980526‚ 21243428‚ 11812557‚ 8696333‚ 9356458‚ 24729993‚ 21349849‚ 19560233‚ 23429074‚ 19159930 Comment: Variant summary: HFE c.187C>G (p.His63Asp) results in a non-conservative amino acid change located in the MHC class I-like antigen recognition-like domain (IPR011161) of the encoded … (more) Variant summary: HFE c.187C>G (p.His63Asp) results in a non-conservative amino acid change located in the MHC class I-like antigen recognition-like domain (IPR011161) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.11 in 251484 control chromosomes in the gnomAD database, including 1832 homozygotes. c.187C>G has been reported as a common disease variant in the literature in individuals affected with Hemochromatosis Type 1, in both homozygous and compound heterozygous states, but most frequently in trans with the most common disease variant c.845G>A (p.Cys282Tyr) (e.g. Feder_1996, Kelley_2014). These data indicate that the variant is likely to be associated with disease, however the variant appears to have very low penetrance, as the majority of homozygous or compound heterozygous individuals with this variant do not exhibit clinical symptoms of hemochromatosis despite some cases having elevated serum ferritin and transferrin saturation levels (e.g. Beutler_2002, Pedersen_2009). Several publications report experimental evidence evaluating an impact on protein function. While p.His63Asp was shown to have normal levels of association with beta2-globulin and expression of HFE on the cell surface in contrast to impairment observed in cells with the other common pathogenic variant p.Cys282Tyr (e.g. Waheed_1997), p.His63Asp was shown to induce ER-stress in-vitro and in a transgenic mouse model (e.g. Liu_2011). Transgenic mice expressing the murine equivalent of this variant were also reported to have increased iron storage and decreased levels of iron mobilization at 12 months of age (e.g. Nandar_2013). The variant has also been reported to alter the expression levels of several genes involved in sphingolipid metabolism (e.g. Ali-Rahmani_2011) and to affect cellular glutamate levels (e.g. Mitchell_2011). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Thirteen of these submitters report the variant as either Pathogenic or a risk factor for disease. Based on the evidence outlined above, the variant was classified as pathogenic with very low penetrance in association with Hemochromatosis. (less)
Pathogenic (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905582.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Clinical Features: Renal insufficiency (present) , Thin skin (present) , Polyneuropathy (present) , Cardiomyopathy (present) , Primary dilated cardiomyopathy (present) Sex: male
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: no Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV002038504.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021	Publications: PubMed (1) PubMed: 26975792 Number of individuals with the variant: 1
Pathogenic (Mar 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502480.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (9) PubMed: 8696333‚ 20560808‚ 17042772‚ 23178241‚ 21349849‚ 17308297‚ 17210810‚ 16186539‚ 15546588 Number of individuals with the variant: 237 Secondary finding: no
Pathogenic (Jan 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Variegate porphyria (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556586.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Comment: Contributing pathogenic variant when co-inherited with other pathogenic variants in HFE or PPOX genes, but not pathogenic alone, even in the homozygous state.
Pathogenic (May 15, 2023)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV004046529.2 First in ClinVar: Oct 21, 2023 Last updated: Dec 17, 2023	Observation 1: Number of individuals with the variant: 1 Clinical Features: Cardiomyopathy (present) Secondary finding: no Observation 2: Clinical Features: Third degree atrioventricular block (present) Secondary finding: no
Pathogenic, low penetrance (Jan 31, 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: SCV000219176.9 First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 28492532‚ 11479183‚ 24729993‚ 11399207‚ 16132052‚ 11358905‚ 9162021‚ 9356458‚ 12429850‚ 14673107 Comment: This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 63 of the HFE protein … (more) This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 63 of the HFE protein (p.His63Asp). This variant is present in population databases (rs1799945, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This is a very common, low penetrance variant that is known to contribute to hemochromatosis when present with a second pathogenic allele in HFE. An estimated 1.5% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 11479183), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes (PMID: 24729993, 11399207, 16132052, 11358905). ClinVar contains an entry for this variant (Variation ID: 10). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HFE protein function. Experimental studies have shown that this missense change affects HFE function (PMID: 9162021, 9356458, 12429850, 14673107). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the HFE gene, it has been classified as Pathogenic (low penetrance). (less)
Pathogenic (May 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Stanford Medicine Accession: SCV004801387.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Comment: • The p.His63Asp variant in the HFE gene has been identified in the homozygous state in approximately 1% of individuals of European ancestry with HFE … (more) • The p.His63Asp variant in the HFE gene has been identified in the homozygous state in approximately 1% of individuals of European ancestry with HFE hemochromatosis, and in the compound heterozygous state with p.Cys282Tyr in approximately 3-8% of individuals of European ancestry with HFE hemochromatosis (Barton and Edwards, 2018). • The p.His63Asp variant is described as a low-penetrant allele and is rarely associated with clinical disease in the homozygous or compound heterozygous state (Gochee et al., 2002; Gurrin et al., 2009). • Individuals heterozygous for the p.His63Asp variant may demonstrate evidence of biochemical disease, including mildly elevated serum transferrin-iron saturation and serum ferritin concentration, but do not develop clinical manifestations of disease (Allen et al., 2008; Pedersen and Milman, 2009). • This variant has been identified in 18,635/129,168 European (non-Finnish) chromosomes (30,592/282,844 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although the p.His63Asp variant is seen at a frequency greater than 5% in the general population, this variant is recognized as a common low-penetrant variant that is an exception to ACMG/AMP classification guidelines (Ghosh et al., 2018). • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.His63Asp variant as pathogenic for autosomal recessive HFE hemochromatosis based on the information above. [ACMG evidence codes used: PS4] (less)
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806939.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Dec 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002506442.2 First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024	Publications: PubMed (1) PubMed: 8696333 Comment: ACMG categories: PS1,PS3,PS4,PP4 Number of individuals with the variant: 1 Clinical Features: Abnormality of iron homeostasis (present) Age: 60-69 years Sex: male Tissue: blood
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002568070.6 First in ClinVar: Sep 03, 2022 Last updated: Aug 04, 2024
Pathogenic (Jan 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198437.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hemochromatosis type 1 Affected status: no Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251532.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 Comment: carrier finding	Publications: PubMed (1) PubMed: 19159930 Bookshelf: NBK1440 Bookshelf: NBK1440 Comment: The HFE c.187C>G (p.H63D) variant is a pathogenic variant seen in 10.8% of the human population in gnomAD. Indviduals with the p.H63D variant are considered … (more) The HFE c.187C>G (p.H63D) variant is a pathogenic variant seen in 10.8% of the human population in gnomAD. Indviduals with the p.H63D variant are considered carriers of hemochromatosis, although this variant is associated with less severe iron overload and reduced penetrance compared to another pathogenic HFE variant, c.845G>A, p.C282Y (PMID: 19159930; 20301613). (less) Number of individuals with the variant: 11
Pathogenic (Mar 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV001984998.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 Comment: Homozygous	Comment: PM3, PP1, PP5, PS4
Pathogenic (Aug 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002028310.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002499222.1 First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022	Comment: PS3, PM3_Strong
Pathogenic (Jul 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV002576301.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769510.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 19554541‚ 26153218 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with haemochromatosis (MIM#235200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The variant has also been shown to have variable phenotypic expression and reduced penetrance (GeneReviews, PMID: 19554541). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v2) at a frequency >5% (26,546 heterozygotes, 2,023 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated class I histocompatibility antigen, domains alpha 1 and 2 (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The is one of the most common, low penetrance variants that has previously been described as pathogenic in multiple patients with haemochromatosis (ClinVar; PMID: 26153218); either in a homozygous state or in trans with p.(Cys282Tyr). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Oct 08, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577565.6 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect (Nandar et al., 2013; Mitchell et al., 2011); This variant is associated with the following publications: (PMID: 19401444, … (more) Published functional studies demonstrate a damaging effect (Nandar et al., 2013; Mitchell et al., 2011); This variant is associated with the following publications: (PMID: 19401444, 20031541, 8696333, 11399207, 31028937, 19159930, 19271219, 24920245, 23389292, 24729993, 20478760, 20640879, 17042772, 25262004, 21925577, 23178241, 19291797, 18525129, 21349849, 19820015, 20097100, 18846434, 23222517, 21514009, 19560233, 24439478, 21243428, 22232660, 20560808, 17450498, 19115475, 11874997, 19554541, 25117103, 26501199, 21909115, 27661980, 26365338, 27153395, 11903355, 17339196, 25687342, 26497867, 28110185, 19214108, 30291871, 11358905, 9356458, 9341868, 20301613, 25767899, 19176287, 18566337, 16132052, 15858186, 15347835, 14729817, 12429850, 11532995, 11479183, 11423500, 31016714, 31180159, 31640930, 23792061, 32014855, 29301508, 31980526, 34426522, 11189980, 11336458, 11478530, 11531973, 9382962, 32641076, 10792295, 10090890, 32874917, 32746448, 23429074) (less)
Pathogenic (May 18, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV000461883.3 First in ClinVar: Dec 06, 2016 Last updated: Jul 22, 2023	Publications: PubMed (5) PubMed: 11874997‚ 19554541‚ 26365338‚ 20301613‚ 8696333 Comment: The HFE c.187C>G (p.His63Asp) missense variant is well described in the literature as a pathogenic variant with significantly reduced penetrance for HFE hemochromatosis. Approximately 1% … (more) The HFE c.187C>G (p.His63Asp) missense variant is well described in the literature as a pathogenic variant with significantly reduced penetrance for HFE hemochromatosis. Approximately 1% of individuals of European ancestry with HFE hemochromatosis are homozygous for the p.His63Asp variant, and between 3-8% are compound heterozygous for the p.His63Asp variant and the well-known p.Cys282Tyr pathogenic variant (PMID: 20301613; PMID: 8696333). Although biochemical abnormalities may be present, only two percent or fewer of individuals who are compound heterozygous for the p.His63Asp variant are expected to develop clinical symptoms of iron overload and HFE hemochromatosis (PMID: 11874997; 19554541; 26365338). Heterozygosity for the p.His63Asp variant ranges from 8.5% in the Asian population to 25% in northern Europeans (PMID: 20301613), with the variant being reported at a frequency of 0.150400 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2), where it is also found in a total of 1005 homozygotes. This allele frequency is high but is consistent with estimates of disease prevalence, reduced penetrance, and a mild phenotype. The p.His63Asp variant is predicted to disrupt a pH-dependent intramolecular salt bridge in the alpha-2 domain, thereby affecting interaction of the protein with the transferrin receptor (PMID: 20301613). Based on the available evidence, the c.187C>G (p.His63Asp) variant is classified as pathogenic for hemochromatosis but with significantly reduced penetrance. (less)
Pathogenic (Dec 27, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Hemochromatosis type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045959.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Myopathy (present) , Mildly elevated creatine kinase (present)
Pathogenic (Dec 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV004183355.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: ACMG classification criteria: PS3, PS4, PM3 Geographic origin: Brazil
Pathogenic (Nov 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001523197.4 First in ClinVar: Mar 22, 2021 Last updated: Dec 24, 2023
Pathogenic (Mar 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV004803201.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: ACMG Criteria: PS1, PS3, PP5; Variant was found in heterozygous state
Pathogenic (Mar 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 Affected status: no Allele origin: biparental	Genomic Medicine Lab, University of California San Francisco Accession: SCV004847117.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Pathogenic (May 23, 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: SCV001715880.3 First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 28280078 Number of individuals with the variant: 62
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hemochromatosis type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005061024.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: The observed missense c.187C>G(p.His63Asp) variant in HFE gene has been reported previously in homozygous or compound heterozygous state in multiple individuals affected with hemochromatosis (Atkins … (more) The observed missense c.187C>G(p.His63Asp) variant in HFE gene has been reported previously in homozygous or compound heterozygous state in multiple individuals affected with hemochromatosis (Atkins et al., 2022), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes. Experimental studies have shown that this missense change affects HFE function (Tomatsu et al., 2003). This variant has been reported with the high allele frequency of 10.9% in the gnomAD Exomes. This variant has been submitted to the ClinVar database with Benign / Uncertain Significance / Risk factor / Pathogenic (multiple submitters). The amino acid His at position 63 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.His63Asp in HFE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.Though the variant frequency is very high in the population, the variant is enriched in patints with HFE hemochromatosis as compared to the general population (Burke et al., 2000). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of the disease. (less) Clinical Features: Abnormality of the cardiovascular system (present)
Pathogenic (Feb 01, 2024)	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: SCV001154674.25 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: HFE: PM3:Strong, PM1, PP4:Moderate, PS3:Moderate, PM2:Supporting Number of individuals with the variant: 118
risk factor (Apr 01, 2019)	no assertion criteria provided Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	Center for Computational Genomics and Data Science, University of Alabama Accession: SCV001142520.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Publications: PubMed (7) PubMed: 12885340‚ 8696333‚ 31220083‚ 28617828‚ 17600748‚ 28443246‚ 30291871 Number of individuals with the variant: 3 Indication for testing: Cystic fibrosis Secondary finding: no
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740600.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	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: SCV001968924.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036308.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (-)	no assertion criteria provided Method: research	Hemochromatosis type 1 Affected status: yes Allele origin: unknown	Genomics And Bioinformatics Analysis Resource, Columbia University Accession: SCV004024108.1 First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 Comment: Compound Heterozygous
Pathogenic (Oct 09, 2023)	no assertion criteria provided Method: clinical testing	Hemochromatosis type 1 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004041642.1 First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001552099.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The HFE p.His63Asp variant is associated with Hereditary Hemochromatosis (HH), an autosomal-recessive disorder caused by pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and … (more) The HFE p.His63Asp variant is associated with Hereditary Hemochromatosis (HH), an autosomal-recessive disorder caused by pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp (Gurrin_2009_PMID: 19554541). This variant was identified in dbSNP (ID: rs1799945), LOVD 3.0 (classified as pathogenic) and ClinVar (classified as pathogenic for hemochromatosis by Invitae, GeneDx, Illumina, Blueprint Genetics, Counsyl, University of Chicago, Partners Laboratory for Molecular Medicine and Knight Diagnostic Laboratories,Oregon Health and Sciences University). The variant was identified in control databases in 30592 of 282844 chromosomes (2023 homozygous) at a frequency of 0.108159 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 18635 of 129168 chromosomes (freq: 0.1443), Other in 872 of 7222 chromosomes (freq: 0.1207), Ashkenazi Jewish in 1113 of 10370 chromosomes (freq: 0.1073), European (Finnish) in 2598 of 25118 chromosomes (freq: 0.1034), Latino in 3556 of 35438 chromosomes (freq: 0.1003), South Asian in 2457 of 30616 chromosomes (freq: 0.08025), East Asian in 680 of 19952 chromosomes (freq: 0.03408) and African in 681 of 24960 chromosomes (freq: 0.02728). Functional studies show that the HFE p.H63D variant impacts brain iron homeostasis (Nandar_2013_PMID: 23429074). Other studies indicate that the presence of the p.H63D variant results in a significant increase in serum transferrin saturation but does not result in significant iron overload and in the absence of the p.C282Y variant, the p.H63D variant is not clinically significant (Goochee_2002_PMID: 11874997). The homozygous state is considered to be extremely low penetrance and associated with variable phenotypes (Kelley_2014_PMID: 24729993). The c.187C>G variant occurs outside of the splicing consensus sequence and the in silico splicing prediction software programs do not predict any difference in splicing (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer). The p.His63 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. References: Gurrin, Lyle C., et al. â€šÃ„ÃºHFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-Related Morbidity.â€šÃ„Ã¹ Hepatology, vol. 50, no. 1, July 2009, pp. 94â€šÃ„Ã¬101. Nandar, Wint, et al. â€šÃ„ÃºA Mutation in the HFE Gene Is Associated with Altered Brain Iron Profiles and Increased Oxidative Stress in Mice.â€šÃ„Ã¹ Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1832, no. 6, 2013, pp. 729â€šÃ„Ã¬741. Gochee, Peter A., et al. â€šÃ„ÃºA Population-Based Study of the Biochemical and Clinical Expression of the H63D Hemochromatosis Mutation.â€šÃ„Ã¹ Gastroenterology, vol. 122, no. 3, 2002, pp. 646â€šÃ„Ã¬651. Kelley, Melissa, et al. â€šÃ„ÃºIron Overload Is Rare in Patients Homozygous for the H63D Mutation.â€šÃ„Ã¹ Canadian Journal of Gastroenterology and Hepatology, vol. 28, no. 4, 2014, pp. 198â€šÃ„Ã¬202. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001927447.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: literature only	Hemochromatosis type 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000245789.3 First in ClinVar: Sep 29, 2015 Last updated: Nov 04, 2023	Publications: Bookshelf: NBK1440 Bookshelf: NBK1440
not provided (Jul 30, 2024)	no classification provided Method: literature only	RECLASSIFIED - HFE POLYMORPHISM Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020169.9 First in ClinVar: Apr 04, 2013 Last updated: Aug 04, 2024	Publications: PubMed (12) PubMed: 12429850‚ 8696333‚ 8896550‚ 11532995‚ 11812557‚ 9106528‚ 11358905‚ 11904676‚ 14673107‚ 11423500‚ 15347835‚ 18566337 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2023. Baltimore, Md. Comment on evidence: This variant has been reclassified as a polymorphism because the H63D variant is present in the gnomAD database (v2.1.1) in 30,592 of 282,855 alleles and … (more) This variant has been reclassified as a polymorphism because the H63D variant is present in the gnomAD database (v2.1.1) in 30,592 of 282,855 alleles and in 2,023 homozygotes, with an allele frequency of 0.1082 (Hamosh, 2023). Drakesmith et al. (2002) used a numbering system beginning with the first amino acid of the mature HFE protein, omitting the 22 amino acids of the signal sequence, so that H63 of the immature protein is H41 in the mature protein. Hemochromatosis, Type 1 In 9 patients with hemochromatosis (HFE1; 235200) who were heterozygous for the C282Y mutation (613609.0001), Feder et al. (1996) identified a C-to-G transversion in exon 2 of the HFE gene, resulting in a his63-to-asp substitution (H63D). This variant was present in 8 of the 9 (89%) nonancestral chromosomes, representing a significant enrichment over the 17% frequency observed in control chromosomes. One patient was homozygous for the H63D variant. An analysis of the H63D mutation in 13 families by Jouanolle et al. (1996) did not support a relationship to HFE. The mutation was present in 3 of 26 heterozygous parents of probands and in each case it was present on the normal chromosome; the analysis of these individuals did not support a compound heterozygous contribution to HFE. In a study of 115 unrelated patients with hereditary hemochromatosis, the UK Haemochromatosis Consortium (1997) found 1 patient who was homozygous for the H63D mutation. However, 3 homozygotes with no evidence of iron overloading were found among 101 control samples derived from healthy blood donors. In addition, compound heterozygosity for the H63D and C232Y mutations was found in 3 patients and 4 controls. Beutler (1997), commenting on the conclusion of Carella et al. (1997) that H63D is a polymorphic change, assembled evidence supporting the likelihood that it is a hemochromatosis-causing mutation with reduced penetrance. He suggested that most of the heterozygotes with mild disease manifestations reported before discovery of the HFE gene will prove, in fact, to be compound heterozygotes for C282Y (613609.0001) and H63D. Aguilar-Martinez et al. (2001) investigated the phenotypic consequences of H63D homozygosity in 56 French homozygotes identified from a series of blood samples submitted for HFE genotyping in response to a confirmed (12) or suspected (38) clinical diagnosis of hemochromatosis or a family history of hemochromatosis (6). Of these, 50 (89%) had evidence of iron overload. In 16 individuals (32%) this appeared to be a phenomenon secondary to dysmetabolic iron overload syndrome, porphyria cutanea tarda, alcohol use, or hepatitis. In the remaining 34 (68%) individuals a secondary cause of iron overload was not identified: 12 had a phenotypic diagnosis of hemochromatosis and the remaining 22 had ill-defined, variable degrees of iron overload with no apparent cause. Extended genetic analysis failed to demonstrate any association between phenotype and other HFE mutations/polymorphisms or the TFR2 Y250X mutation (604720.0001)/TFR2 polymorphisms. The authors commented that, in this selected population, H63D homozygosity was associated with extremely variable phenotypes. They suggested that factors such as age and sex may be important nongenetic phenotypic modifiers. Cardoso et al. (2002) analyzed linkage disequilibrium between HLA alleles and HFE mutations in a Portuguese population. The results confirmed linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. Extensions of these studies showed significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a coselection of H63D and the HLA-A29 allele itself. Insight into the biologic significance of this association was given by the finding of significantly higher CD8+ T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele. To examine whether the HFE H63D mutation is pathogenic, Tomatsu et al. (2003) generated knockin mice homozygous for H67D (corresponding to human H63D), mice homozygous for C294Y (corresponding to human C282Y), and mice compound heterozygous for both mutations. The biochemical and histopathologic severity of hepatic iron loading was significantly increased in all 3 groups compared to control mice, but was less in H67D homozygotes than in compound heterozygotes, and was highest in C294Y homozygotes. Only the C294Y homozygous mice showed a significant increase in transferrin saturation compared to controls. Tomatsu et al. (2003) concluded that the H67D allele, when homozygous or combined with a more severe mutation, leads to partial loss of Hfe function in mice and to increased hepatic iron loading. Microvascular Complications of Diabetes 7, Susceptibility to Moczulski et al. (2001) analyzed the H63D polymorphism in 563 Polish patients with type 2 diabetes (125853) and 196 controls and observed an increased frequency of the 63D allele (odds ratio, 1.8) among patients with diabetic nephropathy (MVCD7; 612635). In a study of 225 Spanish patients with type 2 diabetes, Oliva et al. (2004) found that the prevalence of nephropathy was higher in the group of patients carrying the homozygous D/D genotype compared to the group carrying the wildtype or heterozygous D genotypes. Davis et al. (2008) analyzed H63D and C282Y HFE genotype data for 1,245 Australian patients with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study and found no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses. (less)
not provided (-)	no classification provided Method: phenotyping only	Hereditary hemochromatosis Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749317.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are … (more) Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Healthy (present) Indication for testing: General Interest Age: 80 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2017-07-02 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Abnormality of eye movement (present) , Myopia (present) , Abnormal oral cavity morphology (present) , Abnormal skull morphology (present) , Abnormality of the cardiovascular system … (more) Abnormality of eye movement (present) , Myopia (present) , Abnormal oral cavity morphology (present) , Abnormal skull morphology (present) , Abnormality of the cardiovascular system (present) , Abnormal cardiovascular system morphology (present) , Immunodeficiency (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Feeding difficulties (present) , Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Tall stature (present) , Abnormal curvature of the vertebral column (present) , EEG abnormality (present) , Generalized hypotonia (present) , Seizure (present) , Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) (less) Indication for testing: Diagnostic Age: 30-39 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2017-06-26 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Hyperthyroidism (present) Indication for testing: General Interest Age: 60-69 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2019-10-18 Testing laboratory interpretation: Pathogenic Observation 4: Number of individuals with the variant: 1 Clinical Features: Hyperthyroidism (present) , Compulsive behaviors (present) Indication for testing: Carrier Screening Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-10-19 Testing laboratory interpretation: Pathogenic Observation 5: Number of individuals with the variant: 1 Clinical Features: Abnormal intestine morphology (present) , Abnormal stomach morphology (present) Indication for testing: General Interest\|none appl Age: 20-29 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2020-11-13 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Bronze diabetes Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607203.5 First in ClinVar: Oct 14, 2017 Last updated: Feb 07, 2023	Comment: Variant identified in multiple participants and classified as Pathogenic. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. … (more) Variant identified in multiple participants and classified as Pathogenic. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Myopia (present) Age: 30-39 years Sex: female Method: Genome Sequencing Testing laboratory: Illumina Laboratory Services,Illumina Date variant was reported to submitter: 2014-10-24 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Myopia (present) , Psychotic disorder (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) Age: 50-59 years Sex: male Method: Genome Sequencing Testing laboratory: Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Date variant was reported to submitter: 2014-12-23 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Myopia (present) , Psychotic disorder (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) Age: 50-59 years Sex: male Method: Genome Sequencing Testing laboratory: Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Date variant was reported to submitter: 2014-12-23 Testing laboratory interpretation: Pathogenic Observation 4: Number of individuals with the variant: 1 Clinical Features: Myopia (present) , Conductive hearing impairment (present) , Hearing impairment (present) , Hypertonia (present) , Anxiety (present) , Depression (present) , Short attention span (present) … (more) Myopia (present) , Conductive hearing impairment (present) , Hearing impairment (present) , Hypertonia (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Abnormality of the bladder (present) , Abnormal renal physiology (present) , Abnormality of urine homeostasis (present) , Gingivitis (present) (less) Age: 30-39 years Sex: female Method: Genotyping Panel Testing laboratory: ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories Date variant was reported to submitter: 2014-10-22 Testing laboratory interpretation: Pathogenic Observation 5: Number of individuals with the variant: 1 Clinical Features: Myopia (present) , Ear malformation (present) , Tinnitus (present) , Depression (present) , Abnormality of reproductive system physiology (present) , Gingivitis (present) Age: 50-59 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2020-05-31 Testing laboratory interpretation: Pathogenic Observation 6: Number of individuals with the variant: 1 Clinical Features: Hypertensive disorder (present) , Hypercholesterolemia (present) , Neoplasm of the skin (present) Indication for testing: Diagnostic Age: 60-69 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2019-06-10 Testing laboratory interpretation: Pathogenic Observation 7: Number of individuals with the variant: 1 Clinical Features: Hypertensive disorder (present) , Hypercholesterolemia (present) , Neoplasm of the skin (present) Indication for testing: Diagnostic Age: 60-69 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2019-06-10 Testing laboratory interpretation: Pathogenic Observation 8: Number of individuals with the variant: 1 Clinical Features: Abnormality of the parathyroid physiology (present) , Tinnitus (present) , Seizure (present) , Abnormality of facial musculature (present) , Abnormal EKG (present) , Cardiomyopathy (present) … (more) Abnormality of the parathyroid physiology (present) , Tinnitus (present) , Seizure (present) , Abnormality of facial musculature (present) , Abnormal EKG (present) , Cardiomyopathy (present) , Abnormal cardiovascular system morphology (present) , Asthma (present) , Abnormality of the respiratory system (present) , Restrictive ventilatory defect (present) , Abnormal esophagus morphology (present) , Abnormal stomach morphology (present) , Abnormality of the liver (present) , Autoimmunity (present) , Immunodeficiency (present) , Abnormal inflammatory response (present) , Recurrent oral herpes (present) , Tooth malposition (present) (less) Age: 0-9 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2016-07-04 Testing laboratory interpretation: Pathogenic Observation 9: Number of individuals with the variant: 1 Clinical Features: Overgrowth (present) , Obesity (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Diabetes mellitus type 1 (present) , Hyperthyroidism … (more) Overgrowth (present) , Obesity (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Diabetes mellitus type 1 (present) , Hyperthyroidism (present) , Abnormality of eye movement (present) , Myopia (present) , Hypermetropia (present) , Anxiety (present) , Depression (present) , Hyperhidrosis (present) , Thickened skin (present) , Asthma (present) , Abnormality of the respiratory system (present) , Abnormality of the bladder (present) (less) Age: 40-49 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2020-12-08 Testing laboratory interpretation: Pathogenic Observation 10: Number of individuals with the variant: 1 Clinical Features: Myopia (present) Indication for testing: Carrier Screening Age: 20-29 years Sex: female Method: Genotyping Panel Testing laboratory: Counsyl Date variant was reported to submitter: 2010-05-10 Testing laboratory interpretation: Pathogenic Observation 11: Number of individuals with the variant: 1 Clinical Features: Oral-pharyngeal dysphagia (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Cafe au lait spots, multiple (present) , Fragile skin (present) … (more) Oral-pharyngeal dysphagia (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Cafe au lait spots, multiple (present) , Fragile skin (present) , Abnormal digit morphology (present) , Abnormal cardiovascular system morphology (present) , Asthma (present) , Abnormal esophagus morphology (present) , Abnormal stomach morphology (present) , Abnormality of the liver (present) , Abnormal intestine morphology (present) , Bruising susceptibility (present) , Abnormality of thrombocytes (present) , Abnormal leukocyte morphology (present) (less) Age: 60-69 years Sex: female Method: Single Gene Sequencing Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2018-03-16 Testing laboratory interpretation: Pathogenic Observation 12: Number of individuals with the variant: 1 Clinical Features: Decreased fetal movement (present) , Abnormal delivery (present) , Obesity (present) , Elevated circulating growth hormone concentration (present) , Hyperthyroidism (present) , Anxiety (present) , … (more) Decreased fetal movement (present) , Abnormal delivery (present) , Obesity (present) , Elevated circulating growth hormone concentration (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Asthma (present) , Abnormal esophagus morphology (present) , Abnormality of the bladder (present) , Autoimmunity (present) , Immunodeficiency (present) , Abnormal inflammatory response (present) , Recurrent infections (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Exome Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2018-08-16 Testing laboratory interpretation: Pathogenic Observation 13: Number of individuals with the variant: 1 Clinical Features: Type 2 diabetes mellitus (present) , Hypogonadism (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Cafe au … (more) Type 2 diabetes mellitus (present) , Hypogonadism (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Cafe au lait spots, multiple (present) , Hyperhidrosis (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Abnormality of reproductive system physiology (present) , Abnormal erythrocyte morphology (present) (less) Age: 40-49 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2017-05-11 Testing laboratory interpretation: Pathogenic Observation 14: Number of individuals with the variant: 1 Clinical Features: Abnormality of eye movement (present) , Myopia (present) , Hypermetropia (present) , Abnormal retinal morphology (present) , Abnormal muscle physiology (present) , Cardiac arrhythmia (present) … (more) Abnormality of eye movement (present) , Myopia (present) , Hypermetropia (present) , Abnormal retinal morphology (present) , Abnormal muscle physiology (present) , Cardiac arrhythmia (present) , Hypertensive disorder (present) , Abnormality of the liver (present) , Autoimmunity (present) , Abnormal thrombosis (present) , Fragile teeth (present) (less) Age: 60-69 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2018-11-08 Testing laboratory interpretation: Pathogenic Observation 15: Number of individuals with the variant: 1 Clinical Features: Abnormality of vision (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Memory impairment (present) , Seizure (present) , Motor stereotypies (present) , … (more) Abnormality of vision (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Memory impairment (present) , Seizure (present) , Motor stereotypies (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Abnormality of the upper respiratory tract (present) , Autoimmunity (present) , Abnormality of coagulation (present) , Bruising susceptibility (present) , Epistaxis (present) , Gingivitis (present) , Recurrent oral herpes (present) , Tooth malposition (present) (less) Age: 20-29 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2019-03-14 Testing laboratory interpretation: Pathogenic Observation 16: Number of individuals with the variant: 1 Clinical Features: Abnormality of vision (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Memory impairment (present) , Seizure (present) , Motor stereotypies (present) , … (more) Abnormality of vision (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Memory impairment (present) , Seizure (present) , Motor stereotypies (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Abnormality of the upper respiratory tract (present) , Autoimmunity (present) , Abnormality of coagulation (present) , Bruising susceptibility (present) , Epistaxis (present) , Gingivitis (present) , Recurrent oral herpes (present) , Tooth malposition (present) (less) Age: 20-29 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2019-03-14 Testing laboratory interpretation: Pathogenic Observation 17: Number of individuals with the variant: 1 Clinical Features: Abnormality of vision (present) , Myopia (present) , Ptosis (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Hypertensive disorder (present) , Abnormal esophagus … (more) Abnormality of vision (present) , Myopia (present) , Ptosis (present) , Cardiac arrhythmia (present) , Abnormal EKG (present) , Hypertensive disorder (present) , Abnormal esophagus morphology (present) , Periodontitis (present) (less) Age: 60-69 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2019-03-18 Testing laboratory interpretation: Pathogenic Observation 18: Number of individuals with the variant: 1 Clinical Features: Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Hyperthyroidism (present) , Anxiety (present) , Depression … (more) Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Short attention span (present) , Atrophic scars (present) , Hyperhidrosis (present) , Cutaneous photosensitivity (present) , Hyperextensible skin (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal stomach morphology (present) , Abnormal large intestine morphology (present) , Tooth malposition (present) (less) Indication for testing: Diagnostic Age: 20-29 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-12-28 Testing laboratory interpretation: Pathogenic Observation 19: Number of individuals with the variant: 1 Clinical Features: Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Hyperthyroidism (present) , Anxiety (present) , Depression … (more) Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Short attention span (present) , Atrophic scars (present) , Hyperhidrosis (present) , Cutaneous photosensitivity (present) , Hyperextensible skin (present) , Joint hypermobility (present) , Abnormal muscle physiology (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal stomach morphology (present) , Abnormal large intestine morphology (present) , Tooth malposition (present) (less) Indication for testing: Diagnostic Age: 20-29 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-12-28 Testing laboratory interpretation: Pathogenic Observation 20: Number of individuals with the variant: 1 Clinical Features: Abnormality iris morphology (present) , Atrophic scars (present) , Cafe au lait spots, multiple (present) , Developmental dysplasia of the hip (present) Age: 60-69 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2019-04-24 Testing laboratory interpretation: Pathogenic Observation 21: Number of individuals with the variant: 1 Clinical Features: Hypermetropia (present) , Myopia (present) , Abnormal intestine morphology (present) , Abnormality of reproductive system physiology (present) Age: 50-59 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2018-01-06 Testing laboratory interpretation: Pathogenic Observation 22: Number of individuals with the variant: 1 Clinical Features: Hypermetropia (present) , Myopia (present) , Cafe au lait spots, multiple (present) , Abnormal pattern of respiration (present) , Abnormal stomach morphology (present) , Abnormality … (more) Hypermetropia (present) , Myopia (present) , Cafe au lait spots, multiple (present) , Abnormal pattern of respiration (present) , Abnormal stomach morphology (present) , Abnormality of the bladder (present) (less) Age: 40-49 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2016-10-25 Testing laboratory interpretation: Pathogenic Observation 23: Number of individuals with the variant: 1 Clinical Features: Hypermetropia (present) , Myopia (present) , Cafe au lait spots, multiple (present) , Abnormal pattern of respiration (present) , Abnormal stomach morphology (present) , Abnormality … (more) Hypermetropia (present) , Myopia (present) , Cafe au lait spots, multiple (present) , Abnormal pattern of respiration (present) , Abnormal stomach morphology (present) , Abnormality of the bladder (present) (less) Age: 40-49 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2016-10-25 Testing laboratory interpretation: Pathogenic Observation 24: Number of individuals with the variant: 1 Clinical Features: Ptosis (present) , Hypermetropia (present) , Abnormal lens morphology (present) , Abnormality of eye movement (present) , Hearing impairment (present) , Vertigo (present) , Tinnitus … (more) Ptosis (present) , Hypermetropia (present) , Abnormal lens morphology (present) , Abnormality of eye movement (present) , Hearing impairment (present) , Vertigo (present) , Tinnitus (present) , Hypertensive disorder (present) , Cardiac arrhythmia (present) , Vascular dilatation (present) , Colon cancer (present) (less) Age: 70-79 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2016-07-26 Testing laboratory interpretation: Pathogenic Observation 25: Number of individuals with the variant: 1 Clinical Features: Hyperthyroidism (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Syncope (present) , Abnormal esophagus morphology (present) , Abnormality of urine homeostasis (present) … (more) Hyperthyroidism (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Syncope (present) , Abnormal esophagus morphology (present) , Abnormality of urine homeostasis (present) , Abnormal renal physiology (present) , Abnormality of the bladder (present) , Neoplasm of uterus (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2015-12-04 Testing laboratory interpretation: Pathogenic Observation 26: Number of individuals with the variant: 1 Clinical Features: Prostate neoplasm (present) , Colon cancer (present) , Hyperpigmentation of the skin (present) , Periodontitis (present) , Gingivitis (present) Indication for testing: Diagnostic Age: 70-79 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2021-04-06 Testing laboratory interpretation: Pathogenic Observation 27: Number of individuals with the variant: 1 Clinical Features: Abnormality of vision (present) , Myopia (present) Age: 30-39 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2021-09-06 Testing laboratory interpretation: Pathogenic Observation 28: Number of individuals with the variant: 1 Clinical Features: Abnormality of vision (present) , Myopia (present) Age: 30-39 years Sex: male Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2021-09-06 Testing laboratory interpretation: Pathogenic Observation 29: Number of individuals with the variant: 1 Clinical Features: Myopia (present) , Anxiety (present) , Short attention span (present) , Abnormal esophagus morphology (present) , Abnormal thrombosis (present) , Abnormality of coagulation (present) Age: 40-49 years Sex: female Method: Genotyping Panel Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic Date variant was reported to submitter: 2020-12-02 Testing laboratory interpretation: Pathogenic
Uncertain significance (Mar 05, 2020)	Flagged submission flagged submission (LMM Criteria) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198337.5 First in ClinVar: Jan 30, 2015 Last updated: Jul 06, 2020	Publications: PubMed (4) PubMed: 11874997‚ 19159930‚ 11812557‚ 19554541 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 71
Uncertain significance (Dec 25, 2021)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Older claim that does not account for recent evidence Source: ClinGen	Hemochromatosis type 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002583554.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: A heterozygous missense variation in exon 2 of the HFE gene that results in the amino acid substitution of Aspartic Acid for Histidine at codon … (more) A heterozygous missense variation in exon 2 of the HFE gene that results in the amino acid substitution of Aspartic Acid for Histidine at codon 63 was detected. The observed variant c.187C>G (p.His63Asp) has previously been reported in a patient affected with Hemochromatosis and functional studies have shown that H63D disrupts normal protein function. The variant has a minor allele frequency of 7% and 10% in the 1000 genomes and gnomAD databases respectively. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. (less) Clinical Features: Generalized edema (present) , Cirrhosis of liver (present) , Joint stiffness (present) Age: 60-69 years Sex: male Ethnicity/Population group: Hindu Geographic origin: India Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean > 80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Benign (-)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Not specified Affected status: no Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV001438937.1 First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020	Number of individuals with the variant: 601 Ethnicity/Population group: Arab Geographic origin: Middle East
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Comment:

The c.187C>G (p.His63Asp) missense variant is widely recognized as one of the two most common disease-causing variants in the HFE gene. Compound heterozygotes for p.Cys282Tyr and p.His63Asp are common in the Caucasian population, and together with homozygotes for the p.Cys282Tyr, account for 87% of individuals of European origin with HFE-HH. However, it is important to note that only ~ 0.5%-2.0% of compound heterozygous individuals develop clinical evidence of the disease due to incomplete penetrance (GeneReviews: Seckington et al., 2015; Ramrakhiani and Bacon, 1998; Morrison et al., 2003). In summary, this variant c.187C>G, (p.His63Asp) meets our criteria for Pathogenic.

Comment:

NM_000410.3(HFE):c.187C>G(H63D) is classified as pathogenic in the context of HFE-associated hereditary hemochromatosis. H63D is only associated with clinical hemochromatosis in the presence of some other genetic variant or condition that affects iron metabolism such as the C282Y variant or liver disease. Sources cited for classification include the following: PMID 9462220, 11904676, 11358905, 19159930, 19554541 and 14673107. Classification of NM_000410.3(HFE):c.187C>G(H63D) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Variant summary: HFE c.187C>G (p.His63Asp) results in a non-conservative amino acid change located in the MHC class I-like antigen recognition-like domain (IPR011161) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.11 in 251484 control chromosomes in the gnomAD database, including 1832 homozygotes. c.187C>G has been reported as a common disease variant in the literature in individuals affected with Hemochromatosis Type 1, in both homozygous and compound heterozygous states, but most frequently in trans with the most common disease variant c.845G>A (p.Cys282Tyr) (e.g. Feder_1996, Kelley_2014). These data indicate that the variant is likely to be associated with disease, however the variant appears to have very low penetrance, as the majority of homozygous or compound heterozygous individuals with this variant do not exhibit clinical symptoms of hemochromatosis despite some cases having elevated serum ferritin and transferrin saturation levels (e.g. Beutler_2002, Pedersen_2009). Several publications report experimental evidence evaluating an impact on protein function. While p.His63Asp was shown to have normal levels of association with beta2-globulin and expression of HFE on the cell surface in contrast to impairment observed in cells with the other common pathogenic variant p.Cys282Tyr (e.g. Waheed_1997), p.His63Asp was shown to induce ER-stress in-vitro and in a transgenic mouse model (e.g. Liu_2011). Transgenic mice expressing the murine equivalent of this variant were also reported to have increased iron storage and decreased levels of iron mobilization at 12 months of age (e.g. Nandar_2013). The variant has also been reported to alter the expression levels of several genes involved in sphingolipid metabolism (e.g. Ali-Rahmani_2011) and to affect cellular glutamate levels (e.g. Mitchell_2011). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Thirteen of these submitters report the variant as either Pathogenic or a risk factor for disease. Based on the evidence outlined above, the variant was classified as pathogenic with very low penetrance in association with Hemochromatosis.

Comment:

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 63 of the HFE protein (p.His63Asp). This variant is present in population databases (rs1799945, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This is a very common, low penetrance variant that is known to contribute to hemochromatosis when present with a second pathogenic allele in HFE. An estimated 1.5% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 11479183), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes (PMID: 24729993, 11399207, 16132052, 11358905). ClinVar contains an entry for this variant (Variation ID: 10). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HFE protein function. Experimental studies have shown that this missense change affects HFE function (PMID: 9162021, 9356458, 12429850, 14673107). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the HFE gene, it has been classified as Pathogenic (low penetrance).

Comment:

• The p.His63Asp variant in the HFE gene has been identified in the homozygous state in approximately 1% of individuals of European ancestry with HFE hemochromatosis, and in the compound heterozygous state with p.Cys282Tyr in approximately 3-8% of individuals of European ancestry with HFE hemochromatosis (Barton and Edwards, 2018). • The p.His63Asp variant is described as a low-penetrant allele and is rarely associated with clinical disease in the homozygous or compound heterozygous state (Gochee et al., 2002; Gurrin et al., 2009). • Individuals heterozygous for the p.His63Asp variant may demonstrate evidence of biochemical disease, including mildly elevated serum transferrin-iron saturation and serum ferritin concentration, but do not develop clinical manifestations of disease (Allen et al., 2008; Pedersen and Milman, 2009). • This variant has been identified in 18,635/129,168 European (non-Finnish) chromosomes (30,592/282,844 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although the p.His63Asp variant is seen at a frequency greater than 5% in the general population, this variant is recognized as a common low-penetrant variant that is an exception to ACMG/AMP classification guidelines (Ghosh et al., 2018). • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.His63Asp variant as pathogenic for autosomal recessive HFE hemochromatosis based on the information above. [ACMG evidence codes used: PS4]

Comment:

The HFE c.187C>G (p.H63D) variant is a pathogenic variant seen in 10.8% of the human population in gnomAD. Indviduals with the p.H63D variant are considered carriers of hemochromatosis, although this variant is associated with less severe iron overload and reduced penetrance compared to another pathogenic HFE variant, c.845G>A, p.C282Y (PMID: 19159930; 20301613).

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with haemochromatosis (MIM#235200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. The variant has also been shown to have variable phenotypic expression and reduced penetrance (GeneReviews, PMID: 19554541). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v2) at a frequency >5% (26,546 heterozygotes, 2,023 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated class I histocompatibility antigen, domains alpha 1 and 2 (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The is one of the most common, low penetrance variants that has previously been described as pathogenic in multiple patients with haemochromatosis (ClinVar; PMID: 26153218); either in a homozygous state or in trans with p.(Cys282Tyr). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Published functional studies demonstrate a damaging effect (Nandar et al., 2013; Mitchell et al., 2011); This variant is associated with the following publications: (PMID: 19401444, 20031541, 8696333, 11399207, 31028937, 19159930, 19271219, 24920245, 23389292, 24729993, 20478760, 20640879, 17042772, 25262004, 21925577, 23178241, 19291797, 18525129, 21349849, 19820015, 20097100, 18846434, 23222517, 21514009, 19560233, 24439478, 21243428, 22232660, 20560808, 17450498, 19115475, 11874997, 19554541, 25117103, 26501199, 21909115, 27661980, 26365338, 27153395, 11903355, 17339196, 25687342, 26497867, 28110185, 19214108, 30291871, 11358905, 9356458, 9341868, 20301613, 25767899, 19176287, 18566337, 16132052, 15858186, 15347835, 14729817, 12429850, 11532995, 11479183, 11423500, 31016714, 31180159, 31640930, 23792061, 32014855, 29301508, 31980526, 34426522, 11189980, 11336458, 11478530, 11531973, 9382962, 32641076, 10792295, 10090890, 32874917, 32746448, 23429074)

Comment:

The HFE c.187C>G (p.His63Asp) missense variant is well described in the literature as a pathogenic variant with significantly reduced penetrance for HFE hemochromatosis. Approximately 1% of individuals of European ancestry with HFE hemochromatosis are homozygous for the p.His63Asp variant, and between 3-8% are compound heterozygous for the p.His63Asp variant and the well-known p.Cys282Tyr pathogenic variant (PMID: 20301613; PMID: 8696333). Although biochemical abnormalities may be present, only two percent or fewer of individuals who are compound heterozygous for the p.His63Asp variant are expected to develop clinical symptoms of iron overload and HFE hemochromatosis (PMID: 11874997; 19554541; 26365338). Heterozygosity for the p.His63Asp variant ranges from 8.5% in the Asian population to 25% in northern Europeans (PMID: 20301613), with the variant being reported at a frequency of 0.150400 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2), where it is also found in a total of 1005 homozygotes. This allele frequency is high but is consistent with estimates of disease prevalence, reduced penetrance, and a mild phenotype. The p.His63Asp variant is predicted to disrupt a pH-dependent intramolecular salt bridge in the alpha-2 domain, thereby affecting interaction of the protein with the transferrin receptor (PMID: 20301613). Based on the available evidence, the c.187C>G (p.His63Asp) variant is classified as pathogenic for hemochromatosis but with significantly reduced penetrance.

Comment:

The observed missense c.187C>G(p.His63Asp) variant in HFE gene has been reported previously in homozygous or compound heterozygous state in multiple individuals affected with hemochromatosis (Atkins et al., 2022), however, penetrance of the homozygous genotype is very low and is associated with variable phenotypes. Experimental studies have shown that this missense change affects HFE function (Tomatsu et al., 2003). This variant has been reported with the high allele frequency of 10.9% in the gnomAD Exomes. This variant has been submitted to the ClinVar database with Benign / Uncertain Significance / Risk factor / Pathogenic (multiple submitters). The amino acid His at position 63 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.His63Asp in HFE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.Though the variant frequency is very high in the population, the variant is enriched in patints with HFE hemochromatosis as compared to the general population (Burke et al., 2000). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of the disease.

Comment:

The HFE p.His63Asp variant is associated with Hereditary Hemochromatosis (HH), an autosomal-recessive disorder caused by pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp (Gurrin_2009_PMID: 19554541). This variant was identified in dbSNP (ID: rs1799945), LOVD 3.0 (classified as pathogenic) and ClinVar (classified as pathogenic for hemochromatosis by Invitae, GeneDx, Illumina, Blueprint Genetics, Counsyl, University of Chicago, Partners Laboratory for Molecular Medicine and Knight Diagnostic Laboratories,Oregon Health and Sciences University). The variant was identified in control databases in 30592 of 282844 chromosomes (2023 homozygous) at a frequency of 0.108159 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 18635 of 129168 chromosomes (freq: 0.1443), Other in 872 of 7222 chromosomes (freq: 0.1207), Ashkenazi Jewish in 1113 of 10370 chromosomes (freq: 0.1073), European (Finnish) in 2598 of 25118 chromosomes (freq: 0.1034), Latino in 3556 of 35438 chromosomes (freq: 0.1003), South Asian in 2457 of 30616 chromosomes (freq: 0.08025), East Asian in 680 of 19952 chromosomes (freq: 0.03408) and African in 681 of 24960 chromosomes (freq: 0.02728). Functional studies show that the HFE p.H63D variant impacts brain iron homeostasis (Nandar_2013_PMID: 23429074). Other studies indicate that the presence of the p.H63D variant results in a significant increase in serum transferrin saturation but does not result in significant iron overload and in the absence of the p.C282Y variant, the p.H63D variant is not clinically significant (Goochee_2002_PMID: 11874997). The homozygous state is considered to be extremely low penetrance and associated with variable phenotypes (Kelley_2014_PMID: 24729993). The c.187C>G variant occurs outside of the splicing consensus sequence and the in silico splicing prediction software programs do not predict any difference in splicing (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer). The p.His63 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. References: Gurrin, Lyle C., et al. â€šÃ„ÃºHFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-Related Morbidity.â€šÃ„Ã¹ Hepatology, vol. 50, no. 1, July 2009, pp. 94â€šÃ„Ã¬101. Nandar, Wint, et al. â€šÃ„ÃºA Mutation in the HFE Gene Is Associated with Altered Brain Iron Profiles and Increased Oxidative Stress in Mice.â€šÃ„Ã¹ Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1832, no. 6, 2013, pp. 729â€šÃ„Ã¬741. Gochee, Peter A., et al. â€šÃ„ÃºA Population-Based Study of the Biochemical and Clinical Expression of the H63D Hemochromatosis Mutation.â€šÃ„Ã¹ Gastroenterology, vol. 122, no. 3, 2002, pp. 646â€šÃ„Ã¬651. Kelley, Melissa, et al. â€šÃ„ÃºIron Overload Is Rare in Patients Homozygous for the H63D Mutation.â€šÃ„Ã¹ Canadian Journal of Gastroenterology and Hepatology, vol. 28, no. 4, 2014, pp. 198â€šÃ„Ã¬202.

Comment:

A heterozygous missense variation in exon 2 of the HFE gene that results in the amino acid substitution of Aspartic Acid for Histidine at codon 63 was detected. The observed variant c.187C>G (p.His63Asp) has previously been reported in a patient affected with Hemochromatosis and functional studies have shown that H63D disrupts normal protein function. The variant has a minor allele frequency of 7% and 10% in the 1000 genomes and gnomAD databases respectively. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.

Comment:

Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 11-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Comment:

Variant identified in multiple participants and classified as Pathogenic. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002583554.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
HFE-Related Hemochromatosis.	Adam MP	-	2024	PMID: 20301613
Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis.	Wilk MA	Cold Spring Harbor molecular case studies	2020	PMID: 32014855
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Associations of genetically determined iron status across the phenome: A mendelian randomization study.	Gill D	PLoS medicine	2019	PMID: 31220083
Mutations in the HFE gene can be associated with increased lung disease severity in cystic fibrosis.	Smith DJ	Gene	2019	PMID: 30291871
ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.	Joly P	PloS one	2017	PMID: 28617828
Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection.	Nairz M	Frontiers in cellular and infection microbiology	2017	PMID: 28443246
Pathophysiological consequences and benefits of HFE mutations: 20 years of research.	Hollerer I	Haematologica	2017	PMID: 28280078
Haemochromatosis.	Powell LW	Lancet (London, England)	2016	PMID: 26975792
EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).	Porto G	European journal of human genetics : EJHG	2016	PMID: 26153218
Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.	Gallego CJ	American journal of human genetics	2015	PMID: 26365338
Iron overload is rare in patients homozygous for the H63D mutation.	Kelley M	Canadian journal of gastroenterology & hepatology	2014	PMID: 24729993
A mutation in the HFE gene is associated with altered brain iron profiles and increased oxidative stress in mice.	Nandar W	Biochimica et biophysica acta	2013	PMID: 23429074
Diagnostic utility of HFE variants in Spanish patients: association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia.	Rodríguez-López R	Gene	2013	PMID: 23178241
Mutant HFE H63D protein is associated with prolonged endoplasmic reticulum stress and increased neuronal vulnerability.	Liu Y	The Journal of biological chemistry	2011	PMID: 21349849
Effect of HFE variants on sphingolipid expression by SH-SY5Y human neuroblastoma cells.	Ali-Rahmani F	Neurochemical research	2011	PMID: 21243428
HFE polymorphisms affect cellular glutamate regulation.	Mitchell RM	Neurobiology of aging	2011	PMID: 19560233
Ferritin concentrations in synovial fluid are higher in osteoarthritis patients with HFE gene mutations (C282Y or H63D).	Carroll GJ	Scandinavian journal of rheumatology	2010	PMID: 20560808
HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.	Gurrin LC	Hepatology (Baltimore, Md.)	2009	PMID: 19554541
Genetic screening for HFE hemochromatosis in 6,020 Danish men: penetrance of C282Y, H63D, and S65C variants.	Pedersen P	Annals of hematology	2009	PMID: 19159930
Prevalence, characteristics, and prognostic significance of HFE gene mutations in type 2 diabetes: the Fremantle Diabetes Study.	Davis TM	Diabetes care	2008	PMID: 18566337
Iron-overload-related disease in HFE hereditary hemochromatosis.	Allen KJ	The New England journal of medicine	2008	PMID: 18199861
Association of hemochromatosis with infectious diseases: expanding spectrum.	Khan FA	International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases	2007	PMID: 17600748
HFE H63D polymorphism is increased in patients with amyotrophic lateral sclerosis of Italian origin.	Restagno G	Journal of neurology, neurosurgery, and psychiatry	2007	PMID: 17308297
The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population.	Sutedja NA	Archives of neurology	2007	PMID: 17210810
H63D homozygotes with hyperferritinaemia: Is this genotype, the primary cause of iron overload?	de Diego C	European journal of haematology	2007	PMID: 17042772
Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS.	Goodall EF	Neurology	2005	PMID: 16186539
The molecular genetics of haemochromatosis.	Le Gac G	European journal of human genetics : EJHG	2005	PMID: 16132052
Hemochromatosis and iron-overload screening in a racially diverse population.	Adams PC	The New England journal of medicine	2005	PMID: 15858186
Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences.	Wang XS	Journal of the neurological sciences	2004	PMID: 15546588
The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2.	Oliva R	Endocrine	2004	PMID: 15347835
Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis.	Tomatsu S	Proceedings of the National Academy of Sciences of the United States of America	2003	PMID: 14673107
HFE alleles in an Irish cystic fibrosis population.	Devaney J	Genetic testing	2003	PMID: 12885340
The hemochromatosis protein HFE inhibits iron export from macrophages.	Drakesmith H	Proceedings of the National Academy of Sciences of the United States of America	2002	PMID: 12429850
Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?	Cardoso CS	Immunogenetics	2002	PMID: 11904676
A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation.	Gochee PA	Gastroenterology	2002	PMID: 11874997
Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA.	Beutler E	Lancet (London, England)	2002	PMID: 11812557
Identification of an endogenous RNA transcribed from the antisense strand of the HFE gene.	Thénié AC	Human molecular genetics	2001	PMID: 11532995
HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology.	Hanson EH	American journal of epidemiology	2001	PMID: 11479183
Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy.	Moczulski DK	Diabetes care	2001	PMID: 11423500
Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause?	Aguilar-Martinez P	Gut	2001	PMID: 11358905
Contribution of different HFE genotypes to iron overload disease: a pooled analysis.	Burke W	Genetics in medicine : official journal of the American College of Medical Genetics	2000	PMID: 11399207
A simple genetic test identifies 90% of UK patients with haemochromatosis. The UK Haemochromatosis Consortium.	The U	Gut	1997	PMID: 9462220
Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells.	Waheed A	Proceedings of the National Academy of Sciences of the United States of America	1997	PMID: 9356458
The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression.	Feder JN	The Journal of biological chemistry	1997	PMID: 9162021
Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.	Carella M	American journal of human genetics	1997	PMID: 9106528
Clinical and biochemical abnormalities in people heterozygous for hemochromatosis.	Bulaj ZJ	The New England journal of medicine	1996	PMID: 8943161
Haemochromatosis and HLA-H.	Jouanolle AM	Nature genetics	1996	PMID: 8896550
A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.	Feder JN	Nature genetics	1996	PMID: 8696333
Hamosh, A. Personal Communication. 2023. Baltimore, Md.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HFE	-	-	-	-
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Text-mined citations for rs1799945 ...

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.187C>G (p.His63Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1799945 ...