NM_014585.6(SLC40A1):c.800G>A (p.Gly267Asp) AND Hemochromatosis type 4

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 29, 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:: RCV000005751.6

Allele description [Variation Report for NM_014585.6(SLC40A1):c.800G>A (p.Gly267Asp)]

NM_014585.6(SLC40A1):c.800G>A (p.Gly267Asp)

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.800G>A (p.Gly267Asp)

HGVS:

NC_000002.12:g.189564186C>T
NG_009027.1:g.21626G>A
NM_014585.6:c.800G>AMANE SELECT
NP_055400.1:p.Gly267Asp
NP_055400.1:p.Gly267Asp
LRG_837t1:c.800G>A
LRG_837:g.21626G>A
LRG_837p1:p.Gly267Asp
NC_000002.11:g.190428912C>T
NM_014585.5:c.800G>A
Q9NP59:p.Gly267Asp

Protein change:

G267D; GLY267ASP

Links:

UniProtKB: Q9NP59#VAR_030064; OMIM: 604653.0009; dbSNP: rs104893664

NCBI 1000 Genomes Browser:

rs104893664

Molecular consequence:

NM_014585.6:c.800G>A - 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
SCV000025933	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2005)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001445855	Laboratory of Molecular Genetics and Genomics, Rennes University Hospital	no assertion criteria provided (ACMG Guidelines, 2015)	Likely pathogenic (Jul 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004642207	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16351644, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000025933

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 2005)

germline

literature only

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

SCV001445855

Laboratory of Molecular Genetics and Genomics, Rennes University Hospital

no assertion criteria provided

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 1, 2020)

germline

clinical testing

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

SCV004642207

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 29, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Genetic and clinical heterogeneity of ferroportin disease.

Cremonesi L, Forni GL, Soriani N, Lamagna M, Fermo I, Daraio F, Galli A, Pietra D, Malcovati L, Ferrari M, Camaschella C, Cazzola M.

Br J Haematol. 2005 Dec;131(5):663-70. Erratum in: Br J Haematol. 2006 Mar;132(6):806. Cemonesi, Laura [corrected to Cremonesi, Laura].

PubMed [citation]

PMID:: 16351644

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000025933.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 6 affected members of family of Chinese descent with isolated elevated serum ferritin (HFE4; 606069), Cremonesi et al. (2005) identified heterozygosity for a 1104G-A transition in exon 7 of the SLC40A1 gene, resulting in a gly267-to-asp (G267D) substitution.

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

From Laboratory of Molecular Genetics and Genomics, Rennes University Hospital, SCV001445855.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004642207.1

#	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 replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 267 of the SLC40A1 protein (p.Gly267Asp). This variant is present in population databases (rs104893664, gnomAD 0.05%). This missense change has been observed in individual(s) with isolated hyperferritinemia (PMID: 16351644). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5418). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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: Sep 29, 2024

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