NM_003227.4(TFR2):c.2128_2132del (p.Ile710fs) AND Hereditary hemochromatosis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 15, 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:: RCV001234936.7

Allele description [Variation Report for NM_003227.4(TFR2):c.2128_2132del (p.Ile710fs)]

NM_003227.4(TFR2):c.2128_2132del (p.Ile710fs)

Genes:

LOC113687175:Sharpr-MPRA regulatory region 4647 [Gene]
TFR2:transferrin receptor 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7q22.1

Genomic location:

Preferred name:

NM_003227.4(TFR2):c.2128_2132del (p.Ile710fs)

HGVS:

NC_000007.14:g.100626767_100626771del
NG_007989.1:g.19780_19784del
NG_062456.1:g.262_266del
NM_001206855.3:c.1615_1619del
NM_003227.4:c.2128_2132delMANE SELECT
NP_001193784.1:p.Ile539fs
NP_003218.2:p.Ile710fs
NC_000007.13:g.100224390_100224394del
NM_003227.3:c.2128_2132del

Protein change:

I539fs

Links:

dbSNP: rs765525417

NCBI 1000 Genomes Browser:

rs765525417

Molecular consequence:

NM_001206855.3:c.1615_1619del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003227.4:c.2128_2132del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001407597	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16424658, 23600741, 26029709, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001407597

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 15, 2023)

germline

clinical testing

PubMed (4)
[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

Hemochromatosis and severe iron overload associated with compound heterozygosity for TFR2 R455Q and two novel mutations TFR2 R396X and G792R.

Lee PL, Barton JC.

Acta Haematol. 2006;115(1-2):102-5.

PubMed [citation]

PMID:: 16424658

Variable age of onset and clinical severity in transferrin receptor 2 related haemochromatosis: novel observations.

Bardou-Jacquet E, Cunat S, Beaumont-Epinette MP, Kannengiesser C, Causse X, Sauvion S, Pouliquen B, Deugnier Y, David V, Loréal O, Aguilar-Martinez P, Brissot P, Jouanolle AM.

Br J Haematol. 2013 Jul;162(2):278-81. doi: 10.1111/bjh.12350. Epub 2013 Apr 18. No abstract available.

PubMed [citation]

PMID:: 23600741

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001407597.5

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

Description

This sequence change creates a premature translational stop signal (p.Ile710Alafs*80) in the TFR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 92 amino acid(s) of the TFR2 protein. This variant is present in population databases (rs765525417, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TFR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 961267). This variant disrupts a region of the TFR2 protein in which other variant(s) (p.Trp781*, p.Gly792Arg, p.Phe729Valfs*63) have been determined to be pathogenic (PMID: 16424658, 23600741, 26029709). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 28, 2024

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