rs1799945

chr6-26090951-C-Gchr6-26090951-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PP5_Strong BP4 BS1_Supporting

The NM_000410.4(HFE):c.187C>G(p.His63Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,898 control chromosomes in the GnomAD database, including 15,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other,other (★★). Synonymous variant affecting the same amino acid position (i.e. H63H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (1005 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14272 hom.)
• Consequence: HFE NM_000410.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance; other criteria provided, multiple submitters, no conflicts P:41 U:2 B:1 O:6
• Conservation: PhyloP100: 1.87

Genes affected

HFE (HGNC:4886): (homeostatic iron regulator) The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). It is thought that this protein functions to regulate iron absorption by regulating the interaction of the transferrin receptor with transferrin. The iron storage disorder, hereditary haemochromatosis, is a recessive genetic disorder that results from defects in this gene. [provided by RefSeq, May 2022]

HFE-AS1 (HGNC:):

H2BC4 (HGNC:4757): (H2B clustered histone 4) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Alpha-1 (size 91) in uniprot entity HFE_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000410.4
• PP5: Variant 6-26090951-C-G is Pathogenic according to our data. Variant chr6-26090951-C-G is described in ClinVar as [other, other]. Clinvar id is 10.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=32, Benign=1, Pathogenic_low_penetrance=1, Likely_pathogenic=1, Uncertain_significance=2, not_provided=4, other=1}. Variant chr6-26090951-C-G is described in Lovd as [Likely_pathogenic]. Variant chr6-26090951-C-G is described in Lovd as [Pathogenic]. Variant chr6-26090951-C-G is described in Lovd as [Likely_benign].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015847087). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.102 (15444/152144) while in subpopulation NFE AF= 0.15 (10219/67976). AF 95% confidence interval is 0.148. There are 1005 homozygotes in gnomad4. There are 7371 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HFE	NM_000410.4	c.187C>G	p.His63Asp	missense_variant	2/6	ENST00000357618.10
HFE-AS1	NR_144383.1	n.84G>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HFE	ENST00000357618.10	c.187C>G	p.His63Asp	missense_variant	2/6	1	NM_000410.4	P3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15453 AN: 152026 Hom.: 1005 Cov.: 31

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.0777

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.109 AC: 27472 AN: 251484 Hom.: 1832 AF XY: 0.112 AC XY: 15193 AN XY: 135916

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0347

Gnomad SAS exome AF: 0.0803

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.135 AC: 197513 AN: 1461754 Hom.: 14272 Cov.: 34 AF XY: 0.134 AC XY: 97535 AN XY: 727184

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.0795

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.102 AC: 15444 AN: 152144 Hom.: 1005 Cov.: 31 AF XY: 0.0991 AC XY: 7371 AN XY: 74366

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.0269

Gnomad4 SAS AF: 0.0773

Gnomad4 FIN AF: 0.0959

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.130

Alfa AF: 0.136 Hom.: 1184

Bravo AF: 0.100

TwinsUK AF: 0.143 AC: 530

ALSPAC AF: 0.136 AC: 526

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.151 AC: 1301

ExAC AF: 0.107 AC: 12942

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.146

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance; other

Submissions summary: Pathogenic:41 Uncertain:2 Benign:1 Other:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 1 Pathogenic:25 Uncertain:1 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Mar 09, 2024	ACMG Criteria: PS1, PS3, PP5; Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Program, Stanford Medicine	May 13, 2021	• 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] -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Mar 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 21, 2021	ACMG classification criteria: PS3, PS4, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Dec 16, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Jul 21, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
not provided, no classification provided	literature only	OMIM	Mar 12, 2024	- -
Uncertain significance, flagged submission	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 25, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 25, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 05, 2022	PS3, PM3_Strong -
Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:11 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	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) -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HFE: PM3:Strong, PM1, PP4:Moderate, PS3:Moderate, PM2:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary hemochromatosis Pathogenic:1 Other:1

Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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). -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -

not specified Uncertain:1 Benign:1

Uncertain significance, flagged submission	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 05, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Benign, flagged submission	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Region Ostergotland

Mar 25, 2021

PM3, PP1, PP5, PS4 -

Variegate porphyria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jan 13, 2020

Contributing pathogenic variant when co-inherited with other pathogenic variants in HFE or PPOX genes, but not pathogenic alone, even in the homozygous state. -

Alzheimer disease;C0162532:Variegate porphyria;C0268323:Familial porphyria cutanea tarda;C2673520:Microvascular complications of diabetes, susceptibility to, 7;C3280096:Transferrin serum level quantitative trait locus 2;C3469186:Hemochromatosis type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Abnormality of iron homeostasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 10, 2021

ACMG categories: PS1,PS3,PS4,PP4 -

Cystic fibrosis Other:1

risk factor, no assertion criteria provided

research

Center for Computational Genomics and Data Science, University of Alabama

Apr 01, 2019

- -

Bronze diabetes Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.56	T;T;T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.016	D;T;D;T;D;D;D
Sift4G	Benign	0.15	T;T;T;T;T;T;T
Polyphen		0.15	B;D;B;B;D;B;.
Vest4		0.30
MPC		0.99
ClinPred		0.012	T
GERP RS		3.5
Varity_R		0.45
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1799945; hg19: chr6-26091179; COSMIC: COSV58513169; COSMIC: COSV58513169;