U.S. flag

An official website of the United States government

NM_000410.4(HFE):c.187C>G (p.His63Asp) AND not provided

Germline classification:
Pathogenic; other (12 submissions)
Last evaluated:
Feb 6, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000175607.48

Allele description

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

Genes:
HFE-AS1:HFE antisense RNA 1 [Gene - HGNC]
HFE:homeostatic iron regulator [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p22.2
Genomic location:
Preferred name:
NM_000410.4(HFE):c.187C>G (p.His63Asp)
HGVS:
  • NC_000006.12:g.26090951C>G
  • NG_008720.2:g.8671C>G
  • NM_000410.4:c.187C>GMANE SELECT
  • NM_001300749.3:c.187C>G
  • NM_001384164.1:c.187C>G
  • NM_001406751.1:c.187C>G
  • NM_139003.3:c.187C>G
  • NM_139004.3:c.187C>G
  • NM_139006.3:c.187C>G
  • NM_139007.3:c.77-363C>G
  • NM_139008.3:c.77-363C>G
  • NM_139009.3:c.118C>G
  • NM_139010.3:c.77-1734C>G
  • NM_139011.3:c.77-2168C>G
  • NP_000401.1:p.His63Asp
  • NP_000401.1:p.His63Asp
  • NP_000401.1:p.His63Asp
  • NP_001287678.1:p.His63Asp
  • NP_001287678.1:p.His63Asp
  • NP_001371093.1:p.His63Asp
  • NP_001393680.1:p.His63Asp
  • NP_620572.1:p.His63Asp
  • NP_620573.1:p.His63Asp
  • NP_620575.1:p.His63Asp
  • NP_620578.1:p.His40Asp
  • LRG_748t1:c.187C>G
  • LRG_748:g.8671C>G
  • LRG_748p1:p.His63Asp
  • NC_000006.11:g.26091179C>G
  • NG_008720.1:p.His63Asp
  • NM_000410.3:c.187C>G
  • NM_001300749.2:c.187C>G
  • NM_001300749.2:c.187C>G
  • NM_001384164.1:c.187C>G
  • NM_139011.2:c.77-2168C>G
  • NR_144383.1:n.84G>C
  • Q30201:p.His63Asp
  • c.187C>G(H63D)
Protein change:
H40D; His63Asp
Links:
Genetic Testing Registry (GTR): GTR000021464; Genetic Testing Registry (GTR): GTR000509340; Genetic Testing Registry (GTR): GTR000558915; UniProtKB: Q30201#VAR_004396; OMIM: 613609.0002; dbSNP: rs1799945
NCBI 1000 Genomes Browser:
rs1799945
Molecular consequence:
  • NM_139007.3:c.77-363C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139008.3:c.77-363C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139010.3:c.77-1734C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139011.3:c.77-2168C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000410.4:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001300749.3:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384164.1:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406751.1:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139003.3:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139004.3:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139006.3:c.187C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139009.3:c.118C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_144383.1:n.84G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
Unknown function
Observations:
703

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000227124Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL ClinVar v180209 classification definitions)
other
(Jun 26, 2018)
germlineclinical testing

Citation Link,

SCV000577565GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Oct 8, 2020)
germlineclinical testing

Citation Link,

SCV001154674CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(Feb 1, 2024)
germlineclinical testing

Citation Link,

SCV001552099Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

SCV001715880Mayo Clinic Laboratories, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 25, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001740600Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus
no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001905582Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 15, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001927447Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001968924Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV002036308Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV002502480AiLife Diagnostics, AiLife Diagnostics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 25, 2022)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002568070Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 6, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown348not providednot providednot providednot providedclinical testing
not providedgermlineyes355not providednot provided1not providedclinical testing

Citations

PubMed

Pathophysiological consequences and benefits of HFE mutations: 20 years of research.

Hollerer I, Bachmann A, Muckenthaler MU.

Haematologica. 2017 May;102(5):809-817. doi: 10.3324/haematol.2016.160432. Epub 2017 Mar 9. Review.

PubMed [citation]
PMID:
28280078
PMCID:
PMC5477599

A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.

Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, et al.

Nat Genet. 1996 Aug;13(4):399-408.

PubMed [citation]
PMID:
8696333
See all PubMed Citations (11)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227124.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided348not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided348not providednot providednot provided

From GeneDx, SCV000577565.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Center for Human Genetics Tuebingen, SCV001154674.20

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided118not providednot providedclinical testingnot provided

Description

HFE: PM3:Strong, PM1, PP4:Moderate, PS3:Moderate, PM2:Supporting

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided118not providednot providednot provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552099.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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 laboratory’s criteria to be classified as pathogenic. References: Gurrin, Lyle C., et al. “HFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-Related Morbidity.” Hepatology, vol. 50, no. 1, July 2009, pp. 94–101. Nandar, Wint, et al. “A Mutation in the HFE Gene Is Associated with Altered Brain Iron Profiles and Increased Oxidative Stress in Mice.” Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1832, no. 6, 2013, pp. 729–741. Gochee, Peter A., et al. “A Population-Based Study of the Biochemical and Clinical Expression of the H63D Hemochromatosis Mutation.” Gastroenterology, vol. 122, no. 3, 2002, pp. 646–651. Kelley, Melissa, et al. “Iron Overload Is Rare in Patients Homozygous for the H63D Mutation.” Canadian Journal of Gastroenterology and Hepatology, vol. 28, no. 4, 2014, pp. 198–202.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715880.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740600.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001905582.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot providednot providednot providednot providednot provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001927447.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968924.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036308.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002502480.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided237not providednot providedclinical testing PubMed (10)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided237not providednot providednot provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002568070.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 2, 2024