NM_000410.4(HFE):c.760A>T (p.Lys254Ter) AND Hereditary hemochromatosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 16, 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:: RCV003051883.2

Allele description [Variation Report for NM_000410.4(HFE):c.760A>T (p.Lys254Ter)]

NM_000410.4(HFE):c.760A>T (p.Lys254Ter)

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.760A>T (p.Lys254Ter)

HGVS:

NC_000006.12:g.26092828A>T
NG_008720.2:g.10548A>T
NM_000410.4:c.760A>TMANE SELECT
NM_001300749.3:c.760A>T
NM_001384164.1:c.760A>T
NM_001406751.1:c.751A>T
NM_001406752.1:c.496A>T
NM_139003.3:c.442A>T
NM_139004.3:c.484A>T
NM_139006.3:c.718A>T
NM_139007.3:c.496A>T
NM_139008.3:c.454A>T
NM_139009.3:c.691A>T
NM_139010.3:c.220A>T
NM_139011.3:c.77-291A>T
NP_000401.1:p.Lys254Ter
NP_000401.1:p.Lys254Ter
NP_001287678.1:p.Lys254Ter
NP_001287678.1:p.Lys254Ter
NP_001371093.1:p.Lys254Ter
NP_001393680.1:p.Lys251Ter
NP_001393681.1:p.Lys166Ter
NP_620572.1:p.Lys148Ter
NP_620573.1:p.Lys162Ter
NP_620575.1:p.Lys240Ter
NP_620576.1:p.Lys166Ter
NP_620577.1:p.Lys152Ter
NP_620578.1:p.Lys231Ter
NP_620579.1:p.Lys74Ter
LRG_748t1:c.760A>T
LRG_748:g.10548A>T
LRG_748p1:p.Lys254Ter
NC_000006.11:g.26093056A>T
NM_000410.3:c.760A>T
NM_001300749.2:c.760A>T

Protein change:

K148*

Molecular consequence:

NM_139011.3:c.77-291A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000410.4:c.760A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001300749.3:c.760A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001384164.1:c.760A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001406751.1:c.751A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001406752.1:c.496A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139003.3:c.442A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139004.3:c.484A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139006.3:c.718A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139007.3:c.496A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139008.3:c.454A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139009.3:c.691A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_139010.3:c.220A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary hemochromatosis (HFE)
Identifiers:: MONDO: MONDO:0006507; MedGen: C0392514; OMIM: PS235200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003342006	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 16, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27518069, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003342006

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 16, 2022)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare HFE variants are the most frequent cause of hemochromatosis in non-c282y homozygous patients with hemochromatosis.

Hamdi-Rozé H, Beaumont-Epinette MP, Ben Ali Z, Le Lan C, Loustaud-Ratti V, Causse X, Loreal O, Deugnier Y, Brissot P, Jouanolle AM, Bardou-Jacquet E.

Am J Hematol. 2016 Dec;91(12):1202-1205. doi: 10.1002/ajh.24535. Epub 2016 Aug 22.

PubMed [citation]

PMID:: 27518069

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003342006.2

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

Description

This sequence change creates a premature translational stop signal (p.Lys254*) in the HFE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HFE are known to be pathogenic (PMID: 27518069). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HFE-related conditions. For these reasons, this variant has been classified as 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: Feb 20, 2024

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