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NM_000410.4(HFE):c.314T>C (p.Ile105Thr) AND Hereditary hemochromatosis

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 25, 2021
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:
RCV001322296.4

Allele description [Variation Report for NM_000410.4(HFE):c.314T>C (p.Ile105Thr)]

NM_000410.4(HFE):c.314T>C (p.Ile105Thr)

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.314T>C (p.Ile105Thr)
HGVS:
  • NC_000006.12:g.26091078T>C
  • NG_008720.2:g.8798T>C
  • NM_000410.4:c.314T>CMANE SELECT
  • NM_001300749.3:c.314T>C
  • NM_001384164.1:c.314T>C
  • NM_001406751.1:c.314T>C
  • NM_139003.3:c.314T>C
  • NM_139004.3:c.314T>C
  • NM_139006.3:c.314T>C
  • NM_139007.3:c.77-236T>C
  • NM_139008.3:c.77-236T>C
  • NM_139009.3:c.245T>C
  • NM_139010.3:c.77-1607T>C
  • NM_139011.3:c.77-2041T>C
  • NP_000401.1:p.Ile105Thr
  • NP_000401.1:p.Ile105Thr
  • NP_001287678.1:p.Ile105Thr
  • NP_001287678.1:p.Ile105Thr
  • NP_001371093.1:p.Ile105Thr
  • NP_001393680.1:p.Ile105Thr
  • NP_620572.1:p.Ile105Thr
  • NP_620573.1:p.Ile105Thr
  • NP_620575.1:p.Ile105Thr
  • NP_620578.1:p.Ile82Thr
  • LRG_748t1:c.314T>C
  • LRG_748:g.8798T>C
  • LRG_748p1:p.Ile105Thr
  • NC_000006.11:g.26091306T>C
  • NM_000410.3:c.314T>C
  • NM_001300749.2:c.314T>C
  • Q30201:p.Ile105Thr
Protein change:
I105T; ILE105THR
Links:
UniProtKB: Q30201#VAR_008730; OMIM: 613609.0009; dbSNP: rs28934596
NCBI 1000 Genomes Browser:
rs28934596
Molecular consequence:
  • NM_139007.3:c.77-236T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139008.3:c.77-236T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139010.3:c.77-1607T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_139011.3:c.77-2041T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000410.4:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001300749.3:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384164.1:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406751.1:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139003.3:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139004.3:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139006.3:c.314T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139009.3:c.245T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001513159Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 25, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands.

Barton JC, Sawada-Hirai R, Rothenberg BE, Acton RT.

Blood Cells Mol Dis. 1999 Jun-Aug;25(3-4):147-55.

PubMed [citation]
PMID:
10575540

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001513159.2

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

Description

This sequence change replaces isoleucine with threonine at codon 105 of the HFE protein (p.Ile105Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hemochromatosis (PMID: 10575540). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024