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NM_000410.4(HFE):c.196C>T (p.Arg66Cys) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 26, 2022
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:
RCV002300585.1

Allele description [Variation Report for NM_000410.4(HFE):c.196C>T (p.Arg66Cys)]

NM_000410.4(HFE):c.196C>T (p.Arg66Cys)

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.196C>T (p.Arg66Cys)
HGVS:
  • NC_000006.12:g.26090960C>T
  • NG_008720.2:g.8680C>T
  • NM_000410.4:c.196C>TMANE SELECT
  • NM_001300749.3:c.196C>T
  • NM_001384164.1:c.196C>T
  • NM_001406751.1:c.196C>T
  • NM_139003.3:c.196C>T
  • NM_139004.3:c.196C>T
  • NM_139006.3:c.196C>T
  • NM_139007.3:c.77-354C>T
  • NM_139008.3:c.77-354C>T
  • NM_139009.3:c.127C>T
  • NM_139010.3:c.77-1725C>T
  • NM_139011.3:c.77-2159C>T
  • NP_000401.1:p.Arg66Cys
  • NP_000401.1:p.Arg66Cys
  • NP_001287678.1:p.Arg66Cys
  • NP_001287678.1:p.Arg66Cys
  • NP_001371093.1:p.Arg66Cys
  • NP_001393680.1:p.Arg66Cys
  • NP_620572.1:p.Arg66Cys
  • NP_620573.1:p.Arg66Cys
  • NP_620575.1:p.Arg66Cys
  • NP_620578.1:p.Arg43Cys
  • LRG_748t1:c.196C>T
  • LRG_748:g.8680C>T
  • LRG_748p1:p.Arg66Cys
  • NC_000006.11:g.26091188C>T
  • NM_000410.3:c.196C>T
  • NM_001300749.2:c.196C>T
  • NR_144383.1:n.75G>A
Protein change:
R43C
Links:
dbSNP: rs747739169
NCBI 1000 Genomes Browser:
rs747739169
Molecular consequence:
  • NM_139007.3:c.77-354C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139008.3:c.77-354C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139010.3:c.77-1725C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139011.3:c.77-2159C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000410.4:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001300749.3:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384164.1:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406751.1:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139003.3:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139004.3:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139006.3:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139009.3:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_144383.1:n.75G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002598620Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Sep 26, 2022) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload.

Biasiotto G, Belloli S, Ruggeri G, Zanella I, Gerardi G, Corrado M, Gobbi E, Albertini A, Arosio P.

Clin Chem. 2003 Dec;49(12):1981-8.

PubMed [citation]
PMID:
14633868

Genetic and metabolic factors are associated with increased hepatic iron stores in a selected population of p.Cys282Tyr heterozygotes.

Mariani R, Pelucchi S, Arosio C, Coletti S, Pozzi M, Paolini V, Trombini P, Piperno A.

Blood Cells Mol Dis. 2010 Mar 15;44(3):159-63. doi: 10.1016/j.bcmd.2010.01.002. Epub 2010 Feb 8.

PubMed [citation]
PMID:
20117027

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002598620.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: HFE c.196C>T (p.Arg66Cys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251490 control chromosomes (gnomAD). The variant, c.196C>T, has been reported in the literature in heterozygous state in an individual with altered iron status (Biasiotto_2003), and in 2 brothers affected with iron overload, both of whom also carried a common, low penetrance disease variant (c.845G>A (p.Cys282Tyr)), however the phase of the two variants was not determined (Mariani_2010). These reports do not provide unequivocal conclusions about association of the variant with Hemochromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Apr 15, 2024