NM_014585.6(SLC40A1):c.190T>C (p.Tyr64His) AND Hemochromatosis type 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 16, 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:: RCV001228946.7

Allele description [Variation Report for NM_014585.6(SLC40A1):c.190T>C (p.Tyr64His)]

NM_014585.6(SLC40A1):c.190T>C (p.Tyr64His)

Gene:

SLC40A1:solute carrier family 40 member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q32.2

Genomic location:

Preferred name:

NM_014585.6(SLC40A1):c.190T>C (p.Tyr64His)

HGVS:

NC_000002.12:g.189575242A>G
NG_009027.1:g.10570T>C
NM_014585.6:c.190T>CMANE SELECT
NP_055400.1:p.Tyr64His
LRG_837t1:c.190T>C
LRG_837:g.10570T>C
NC_000002.11:g.190439968A>G
NM_014585.5:c.190T>C

Protein change:

Y64H

Links:

dbSNP: rs1285653301

NCBI 1000 Genomes Browser:

rs1285653301

Molecular consequence:

NM_014585.6:c.190T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hemochromatosis type 4 (HFE4)
Synonyms:: Hemochromatosis, autosomal dominant; Hemochromatosis due to defect in ferroportin
Identifiers:: MONDO: MONDO:0011631; MedGen: C1853733; Orphanet: 139491; OMIM: 606069

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001401376	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 16, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12857562, 25396007, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001401376

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 16, 2021)

germline

clinical testing

PubMed (3)
[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

Autosomal dominant reticuloendothelial iron overload (HFE type 4) due to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a large French-Canadian family.

Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R, Simard R, D'Adamo AP, De Braekeleer M, Gasparini P.

Haematologica. 2003 Jul;88(7):824-6. No abstract available.

PubMed [citation]

PMID:: 12857562

Raszeja-Wyszomirska J, Caleffi A, Milkiewicz P, Pietrangelo A.

Prz Gastroenterol. 2014;9(5):307-9. doi: 10.5114/pg.2014.46167. Epub 2014 Oct 19.

PubMed [citation]

PMID:: 25396007
PMCID:: PMC4223120

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001401376.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. This variant disrupts the p.Tyr64 amino acid residue in SLC40A1 (also referred to as SLC11A3). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12857562). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with ferroportin disease (PMID: 25396007). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 64 of the SLC40A1 protein (p.Tyr64His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.

#	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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