NM_003227.4(TFR2):c.2014C>T (p.Gln672Ter) AND Hemochromatosis type 3

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 19, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000779521.13

Allele description [Variation Report for NM_003227.4(TFR2):c.2014C>T (p.Gln672Ter)]

NM_003227.4(TFR2):c.2014C>T (p.Gln672Ter)

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

7q22.1

Genomic location:

Preferred name:

NM_003227.4(TFR2):c.2014C>T (p.Gln672Ter)

HGVS:

NC_000007.14:g.100626885G>A
NG_007989.1:g.19666C>T
NG_062456.1:g.380G>A
NM_001206855.3:c.1501C>T
NM_003227.4:c.2014C>TMANE SELECT
NP_001193784.1:p.Gln501Ter
NP_003218.2:p.Gln672Ter
NC_000007.13:g.100224508G>A
NM_003227.3:c.2014C>T

Protein change:

Q501*

Links:

dbSNP: rs1051249273

NCBI 1000 Genomes Browser:

rs1051249273

Molecular consequence:

NM_001206855.3:c.1501C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003227.4:c.2014C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hemochromatosis type 3 (HFE3)
Synonyms:: Hemochromatosis due to defect in transferrin receptor 2; Hereditary hemochromatosis type 3; TFR2-Related Hereditary Hemochromatosis
Identifiers:: MONDO: MONDO:0011417; MedGen: C1858664; Orphanet: 225123; OMIM: 604250

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916168	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Oct 15, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002018955	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002079929	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 5, 2021)	germline	clinical testing
SCV004203687	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3.

Joshi R, Shvartsman M, Morán E, Lois S, Aranda J, Barqué A, de la Cruz X, Bruguera M, Vagace JM, Gervasini G, Sanz C, Sánchez M.

Mol Genet Genomic Med. 2015 May;3(3):221-32. doi: 10.1002/mgg3.136. Epub 2015 Mar 6.

PubMed [citation]

PMID:: 26029709
PMCID:: PMC4444164

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916168.1

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

Description

The TFR2 c.2014C>T (p.Gln672Ter) variant is a stop-gained variant, that has been reported in one study and is found in a compound heterozygous state with another stop-gained variant in a single individual with hereditary hemochromatosis (Joshi et al. 2015). The variant is also found in two unaffected family members in a heterozygous state. Control data are unavailable for the p.Gln672Ter variant and is reported at a frequency of 0.000293 in the Latino population of the Genome Aggregation Database. Based on the evidence and due to the potential impact of stop-gained variants, the p.Gln672Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for hereditary hemochromatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

From Revvity Omics, Revvity, SCV002018955.3

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

#	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

From Natera, Inc., SCV002079929.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Baylor Genetics, SCV004203687.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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