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

Germline classification:: risk factor (1 submission)
Last evaluated:: Mar 4, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003493406.1

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:

Condition(s)

Name:: Juvenile hemochromatosis
Synonyms:: Hemochromatosis type 2
Identifiers:: MONDO: MONDO:0019257; MedGen: C0268060

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221190	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	risk factor (Mar 4, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11812557, 19554541, 19444013, 19159930, 21243428, 22531912, 17828789, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000221190

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

risk factor
(Mar 4, 2020)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	53	51	not provided	not provided	not provided	clinical testing

Citations

PubMed

Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA.

Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T.

Lancet. 2002 Jan 19;359(9302):211-8.

PubMed [citation]

PMID:: 11812557

HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.

Gurrin LC, Bertalli NA, Dalton GW, Osborne NJ, Constantine CC, McLaren CE, English DR, Gertig DM, Delatycki MB, Nicoll AJ, Southey MC, Hopper JL, Giles GG, Anderson GJ, Olynyk JK, Powell LW, Allen KJ; HealthIron Study Investigators..

Hepatology. 2009 Jul;50(1):94-101. doi: 10.1002/hep.22972.

PubMed [citation]

PMID:: 19554541
PMCID:: PMC3763940

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000221190.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	53	not provided	not provided	clinical testing	PubMed (8)

Description

HFE c.845G>A (p.Cys282Tyr) has been associated with increased risk for hemochromatosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (5.7%, Genome Aggregation Database (gnomAD); rs1800562) and is present in ClinVar (ID: 9). A large meta-analysis has reported an odds ratio of 1.2 [95% CI 0.8-1.6] for developing liver disease in heterozygous carriers (Ellervik 2007). In vitro and in vivo functional studies provide some evidence that this variant may impact protein function (Ali-Rahmani 2011, Boucherma 2012). In summary, this variant is uncertain risk allele for hemochromatosis in heterozygous state. HFE c.845G>A (p.Cys282Tyr) has been associated with increased risk for hemochromatosis. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (5.7%, Genome Aggregation Database (gnomAD); rs1800562) and is present in ClinVar (ID: 9). A large meta-analysis has reported an odds ratio of 3.9 [95% CI 1.9-8.1] for developing liver disease in homozygous carriers (Ellervik 2007). In vitro and in vivo functional studies provide some evidence that this variant may impact protein function (Ali-Rahmani 2011, Boucherma 2012). In summary, this variant is established risk allele for hemochromatosis in homozygous state.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		53	not provided	51	not provided

Last Updated: Oct 8, 2024

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