NM_000410.4(HFE):c.848A>C (p.Gln283Pro) AND Hemochromatosis type 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 3, 2023
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:: RCV000000036.7

Allele description [Variation Report for NM_000410.4(HFE):c.848A>C (p.Gln283Pro)]

NM_000410.4(HFE):c.848A>C (p.Gln283Pro)

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.848A>C (p.Gln283Pro)

HGVS:

NC_000006.12:g.26092916A>C
NG_008720.2:g.10636A>C
NM_000410.4:c.848A>CMANE SELECT
NM_001300749.3:c.848A>C
NM_001384164.1:c.848A>C
NM_001406751.1:c.839A>C
NM_001406752.1:c.584A>C
NM_139003.3:c.530A>C
NM_139004.3:c.572A>C
NM_139006.3:c.806A>C
NM_139007.3:c.584A>C
NM_139008.3:c.542A>C
NM_139009.3:c.779A>C
NM_139010.3:c.308A>C
NM_139011.3:c.77-203A>C
NP_000401.1:p.Gln283Pro
NP_000401.1:p.Gln283Pro
NP_001287678.1:p.Gln283Pro
NP_001287678.1:p.Gln283Pro
NP_001371093.1:p.Gln283Pro
NP_001393680.1:p.Gln280Pro
NP_001393681.1:p.Gln195Pro
NP_620572.1:p.Gln177Pro
NP_620573.1:p.Gln191Pro
NP_620575.1:p.Gln269Pro
NP_620576.1:p.Gln195Pro
NP_620577.1:p.Gln181Pro
NP_620578.1:p.Gln260Pro
NP_620579.1:p.Gln103Pro
LRG_748t1:c.848A>C
LRG_748:g.10636A>C
LRG_748p1:p.Gln283Pro
NC_000006.11:g.26093144A>C
NM_000410.3:c.848A>C
NM_001300749.2:c.848A>C
Q30201:p.Gln283Pro

Protein change:

Q103P; GLN283PRO

Links:

UniProtKB: Q30201#VAR_037304; OMIM: 613609.0011; dbSNP: rs111033563

NCBI 1000 Genomes Browser:

rs111033563

Molecular consequence:

NM_139011.3:c.77-203A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000410.4:c.848A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001300749.3:c.848A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384164.1:c.848A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406751.1:c.839A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406752.1:c.584A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139003.3:c.530A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139004.3:c.572A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139006.3:c.806A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139007.3:c.584A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139008.3:c.542A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139009.3:c.779A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139010.3:c.308A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hemochromatosis type 1 (HFE1)
Synonyms:: HFE-Associated Hereditary Hemochromatosis
Identifiers:: MONDO: MONDO:0021001; MedGen: C3469186; OMIM: 235200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020179	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2005)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9546397, 15965644
SCV004028688	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 3, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25850353, 33791166, 15965644, 12737937 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020179

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 2005)

germline

literature only

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

SCV004028688

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 3, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.

Lebrón JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ.

Cell. 1998 Apr 3;93(1):111-23.

PubMed [citation]

PMID:: 9546397

Compound heterozygous C282Y/Q283P and Q283P/H63D mutations in haemochromatosis.

van Gammeren A, de Baar E, Schrauwen L, van Wijngaarden P.

Br J Haematol. 2015 Nov;171(4):650-1. doi: 10.1111/bjh.13417. Epub 2015 Apr 8. No abstract available.

PubMed [citation]

PMID:: 25850353

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000020179.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected members of a French family with hemochromatosis (235200), Le Gac et al. (2003) identified compound heterozygosity for 2 mutations in the HFE gene: an 848A-C transversion in exon 4, resulting in a gln283-to-pro (Q283P) substitution within the alpha-3 domain, and a C282Y (613609.0001) substitution. Molecular modeling studies predicted a destabilizing effect for the Q283P substitution on the tertiary structure of the protein.

By performing immunoprecipitation studies in HeLa cells, Ka et al. (2005) found that the Q283P mutation prevented the normal interaction between HFE protein and beta-2-microglobulin (B2M; 109700) and between HFE protein and transferrin receptor (TFRC; 190010). Further studies showed that the Q283P mutation decreased the capacity of HFE to reduce transferrin-mediated iron uptake. Ka et al. (2005) noted that the Q283P mutation is adjacent to the disulfide bridge formed by cys225 and cys282, and concluded that the Q283P protein is retained in the endoplasmic reticulum and middle Golgi compartments, similar to the C282Y mutant protein. The results indicated that the Q283P mutation leads to structural and functional consequences similar to those described for the more common C282Y mutation.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004028688.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: HFE c.848A>C (p.Gln283Pro) results in a non-conservative amino acid change located in the Immunoglobulin C1-set domain (IPR003597) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251294 control chromosomes. c.848A>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Hemochromatosis Type 1 (example, LeGac_2003, van Gammeren_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a highly reduced capacity of mutant HFE to reduce transferrin-mediated iron uptake and abolished ability to form complexes with beta2 microglobulin and Transferrin 1 (Ka_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15965644, 12737937, 33791166, 25850353). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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