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NM_000410.4(HFE):c.50C>T (p.Thr17Ile) AND Hereditary hemochromatosis

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jul 20, 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:
RCV000538099.5

Allele description

NM_000410.4(HFE):c.50C>T (p.Thr17Ile)

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.50C>T (p.Thr17Ile)
HGVS:
  • NC_000006.12:g.26087490C>T
  • NG_008720.2:g.5210C>T
  • NM_000410.4:c.50C>TMANE SELECT
  • NM_001300749.3:c.50C>T
  • NM_001384164.1:c.50C>T
  • NM_001406751.1:c.50C>T
  • NM_001406752.1:c.50C>T
  • NM_139003.3:c.50C>T
  • NM_139004.3:c.50C>T
  • NM_139006.3:c.50C>T
  • NM_139007.3:c.50C>T
  • NM_139008.3:c.50C>T
  • NM_139009.3:c.50C>T
  • NM_139010.3:c.50C>T
  • NM_139011.3:c.50C>T
  • NP_000401.1:p.Thr17Ile
  • NP_000401.1:p.Thr17Ile
  • NP_001287678.1:p.Thr17Ile
  • NP_001287678.1:p.Thr17Ile
  • NP_001371093.1:p.Thr17Ile
  • NP_001393680.1:p.Thr17Ile
  • NP_001393681.1:p.Thr17Ile
  • NP_620572.1:p.Thr17Ile
  • NP_620573.1:p.Thr17Ile
  • NP_620575.1:p.Thr17Ile
  • NP_620576.1:p.Thr17Ile
  • NP_620577.1:p.Thr17Ile
  • NP_620578.1:p.Thr17Ile
  • NP_620579.1:p.Thr17Ile
  • NP_620580.1:p.Thr17Ile
  • LRG_748t1:c.50C>T
  • LRG_748:g.5210C>T
  • LRG_748p1:p.Thr17Ile
  • NC_000006.11:g.26087718C>T
  • NM_000410.3:c.50C>T
  • NM_001300749.2:c.50C>T
  • NR_144383.1:n.985G>A
Protein change:
T17I
Links:
dbSNP: rs143662783
NCBI 1000 Genomes Browser:
rs143662783
Molecular consequence:
  • NM_000410.4:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001300749.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001384164.1:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406751.1:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406752.1:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139003.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139004.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139006.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139007.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139008.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139009.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139010.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139011.3:c.50C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_144383.1:n.985G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000633734Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jul 20, 2022) 		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

Next-generation sequencing: Application of a novel platform to analyze atypical iron disorders.

McDonald CJ, Ostini L, Wallace DF, Lyons A, Crawford DH, Subramaniam VN.

J Hepatol. 2015 Nov;63(5):1288-93. doi: 10.1016/j.jhep.2015.06.027. Epub 2015 Jul 4. Review.

PubMed [citation]
PMID:
26151776

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 Invitae, SCV000633734.3

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

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 17 of the HFE protein (p.Thr17Ile). This variant is present in population databases (rs143662783, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with iron overload (PMID: 26151776). ClinVar contains an entry for this variant (Variation ID: 461193). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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: Mar 30, 2024