NM_000410.4(HFE):c.845G>A (p.Cys282Tyr) AND Hereditary hemochromatosis

Germline classification:
Pathogenic/Pathogenic, low penetrance (4 submissions)
Last evaluated:
Jan 31, 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:
RCV000308358.27

Allele description [Variation Report for NM_000410.4(HFE):c.845G>A (p.Cys282Tyr)]

NM_000410.4(HFE):c.845G>A (p.Cys282Tyr)

Gene:
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.845G>A (p.Cys282Tyr)
HGVS:
  • NC_000006.12:g.26092913G>A
  • NG_008720.2:g.10633G>A
  • NM_000410.4:c.845G>AMANE SELECT
  • NM_001300749.3:c.845G>A
  • NM_001384164.1:c.845G>A
  • NM_001406751.1:c.836G>A
  • NM_001406752.1:c.581G>A
  • NM_139003.3:c.527G>A
  • NM_139004.3:c.569G>A
  • NM_139006.3:c.803G>A
  • NM_139007.3:c.581G>A
  • NM_139008.3:c.539G>A
  • NM_139009.3:c.776G>A
  • NM_139010.3:c.305G>A
  • NM_139011.3:c.77-206G>A
  • NP_000401.1:p.Cys282Tyr
  • NP_000401.1:p.Cys282Tyr
  • NP_001287678.1:p.Cys282Tyr
  • NP_001287678.1:p.Cys282Tyr
  • NP_001371093.1:p.Cys282Tyr
  • NP_001393680.1:p.Cys279Tyr
  • NP_001393681.1:p.Cys194Tyr
  • NP_620572.1:p.Cys176Tyr
  • NP_620573.1:p.Cys190Tyr
  • NP_620575.1:p.Cys268Tyr
  • NP_620576.1:p.Cys194Tyr
  • NP_620577.1:p.Cys180Tyr
  • NP_620578.1:p.Cys259Tyr
  • NP_620579.1:p.Cys102Tyr
  • LRG_748t1:c.845G>A
  • LRG_748:g.10633G>A
  • LRG_748p1:p.Cys282Tyr
  • NC_000006.11:g.26093141G>A
  • NG_008720.1:p.Cys282Tyr
  • NM_000410.3:c.845G>A
  • NM_000410.3:c.845G>A
  • NM_000410.4:c.845G>A
  • NM_001300749.2:c.845G>A
  • Q30201:p.Cys282Tyr
  • c.845G>A(C282Y)
Protein change:
C102Y; Cys282Tyr
Links:
Genetic Testing Registry (GTR): GTR000021464; Genetic Testing Registry (GTR): GTR000509340; Genetic Testing Registry (GTR): GTR000558915; UniProtKB: Q30201#VAR_004398; OMIM: 613609.0001; dbSNP: rs1800562
NCBI 1000 Genomes Browser:
rs1800562
Molecular consequence:
  • NM_139011.3:c.77-206G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000410.4:c.845G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001300749.3:c.845G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384164.1:c.845G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406751.1:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406752.1:c.581G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139003.3:c.527G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139004.3:c.569G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139006.3:c.803G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139007.3:c.581G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139008.3:c.539G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139009.3:c.776G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139010.3:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Hereditary hemochromatosis (HFE)
Identifiers:
MONDO: MONDO:0006507; MedGen: C0392514; OMIM: PS235200

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000219175Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic, low penetrance
(Jan 31, 2024) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001749341GenomeConnect - Invitae Patient Insights Network
no classification provided
not providedunknownphenotyping only

SCV002061285DASA
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 5, 2022) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV003931195GenomeConnect - Brain Gene Registry
no classification provided
not providedbiparentalphenotyping only

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedbiparentalunknown1not providednot provided1not providedphenotyping only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes2not providednot providednot providednot providedclinical testing
not providedunknownunknown2not providednot provided2not providedphenotyping only

Citations

PubMed

The molecular genetics of haemochromatosis.

Le Gac G, Férec C.

Eur J Hum Genet. 2005 Nov;13(11):1172-85. Review.

PubMed [citation]
PMID:
16132052

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

Porto G, Brissot P, Swinkels DW, Zoller H, Kamarainen O, Patton S, Alonso I, Morris M, Keeney S.

Eur J Hum Genet. 2016 Apr;24(4):479-95. doi: 10.1038/ejhg.2015.128. Epub 2015 Jul 8.

PubMed [citation]
PMID:
26153218
PMCID:
PMC4929861
See all PubMed Citations (16)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000219175.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 282 of the HFE protein (p.Cys282Tyr). This variant is present in population databases (rs1800562, gnomAD 6%), and has an allele count higher than expected for a pathogenic variant. This is a common, low penetrance variant that is known to contribute to hemochromatosis when homozygous or present with a second pathogenic allele in HFE. As many as 90% of individuals of European descent who are affected with hemochromatosis are homozygous for this variant (PMID: 16132052, 26153218, 26365338). ClinVar contains an entry for this variant (Variation ID: 9). 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) performed at Invitae indicates that this missense variant is expected to disrupt HFE protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change disrupts a disulfide bond in the α3 domain of the HFE protein and impairs interaction of HFE with beta2-microglobulin, resulting in a block in intracellular transport and loss of cell surface expression of the Cys282Tyr variant protein (PMID: 9162021, 9356458). 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).

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

From GenomeConnect - Invitae Patient Insights Network, SCV001749341.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedphenotyping onlynot provided
2not provided1not providednot providedphenotyping onlynot provided

Description

Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 11/20/2019 by Illumina and 6/19/2020 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknown1not providednot provided1not providednot providednot provided
2unknownunknown1not providednot provided1not providednot providednot provided

From DASA, SCV002061285.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (13)

Description

The c.845G>A;p.(Cys282Tyr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9; OMIM: 613609.0001; PMID: 20301613; 27659401; 26365338; 19084217; 11040194; 23953397; 26365338) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11040194; 23953397; 9162021; 9356458) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Immunoglobulin C1-set domain) - PM1. The p.(Cys282Tyr) was detected in trans with a pathogenic variant (PMID: 15507752; 17384005; 26244503; 25850353; 25277871; 24401005; 23953397; 32153640; 11478530; 26365338) - PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 32153640; 11478530) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From GenomeConnect - Brain Gene Registry, SCV003931195.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedphenotyping onlynot provided

Description

Variant classified as Pathogenic and reported on 05-24-2022 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1biparentalunknown1not providednot provided1not providednot providednot provided

Last Updated: Oct 8, 2024