NM_014585.6(SLC40A1):c.697C>G (p.Leu233Val) AND Hemochromatosis type 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 16, 2019
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:: RCV001204731.8

Allele description [Variation Report for NM_014585.6(SLC40A1):c.697C>G (p.Leu233Val)]

NM_014585.6(SLC40A1):c.697C>G (p.Leu233Val)

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.697C>G (p.Leu233Val)

HGVS:

NC_000002.12:g.189565417G>C
NG_009027.1:g.20395C>G
NM_014585.6:c.697C>GMANE SELECT
NP_055400.1:p.Leu233Val
LRG_837t1:c.697C>G
LRG_837:g.20395C>G
NC_000002.11:g.190430143G>C
NM_014585.5:c.697C>G
p.Leu233Val

Protein change:

L233V

Links:

dbSNP: rs186912553

NCBI 1000 Genomes Browser:

rs186912553

Molecular consequence:

NM_014585.6:c.697C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001335599	Dept of Medicine and Surgery, University of Milano-Bicocca	no assertion criteria provided	Pathogenic (Nov 20, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001375950	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 16, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001335599

Dept of Medicine and Surgery, University of Milano-Bicocca

no assertion criteria provided

Pathogenic
(Nov 20, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001375950

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 16, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
Caucasian	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ferroportin disease: A novel SLC40A1 mutation.

Ravasi G, Pelucchi S, Russo A, Mariani R, Piperno A.

Dig Liver Dis. 2020 Jun;52(6):688-690. doi: 10.1016/j.dld.2020.03.013. Epub 2020 Apr 29. No abstract available.

PubMed [citation]

PMID:: 32360131

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 Dept of Medicine and Surgery, University of Milano-Bicocca, SCV001335599.1

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

From Invitae, SCV001375950.5

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

Description

This variant has not been reported in the literature in individuals with SLC40A1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 233 of the SLC40A1 protein (p.Leu233Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine.

#	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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