NM_014585.6(SLC40A1):c.610G>A (p.Gly204Ser) AND Hemochromatosis type 4

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jul 23, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000641707.10

Allele description [Variation Report for NM_014585.6(SLC40A1):c.610G>A (p.Gly204Ser)]

NM_014585.6(SLC40A1):c.610G>A (p.Gly204Ser)

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.610G>A (p.Gly204Ser)

HGVS:

NC_000002.12:g.189565504C>T
NG_009027.1:g.20308G>A
NM_014585.6:c.610G>AMANE SELECT
NP_055400.1:p.Gly204Ser
NP_055400.1:p.Gly204Ser
LRG_837t1:c.610G>A
LRG_837:g.20308G>A
LRG_837p1:p.Gly204Ser
NC_000002.11:g.190430230C>T
NM_014585.5:c.610G>A

Protein change:

G204S

Links:

dbSNP: rs387907377

NCBI 1000 Genomes Browser:

rs387907377

Molecular consequence:

NM_014585.6:c.610G>A - 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
SCV000763355	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23943237, 21199650, 31640930, 28492532
SCV000894249	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001445849	Laboratory of Molecular Genetics and Genomics, Rennes University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 1, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21199650, 25741868
SCV002318955	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23943237, 21199650, 21411349, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
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

Mutations and polymorphisms associated with iron overload in a series of 91 non-HFE haemochromatosis patients.

Borgel A, Lamoril J, Tchernitchko D.

Clin Res Hepatol Gastroenterol. 2020 Apr;44(2):239-241. doi: 10.1016/j.clinre.2019.09.007. Epub 2019 Oct 19. No abstract available.

PubMed [citation]

PMID:: 31640930

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Invitae, SCV000763355.5

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

Description

This variant is present in population databases (rs387907377, gnomAD 0.006%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC40A1 function (PMID: 23943237). 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"). ClinVar contains an entry for this variant (Variation ID: 56158). This missense change has been observed in individuals with hemochromatosis (PMID: 21199650, 31640930). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 204 of the SLC40A1 protein (p.Gly204Ser).

#	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 Fulgent Genetics, Fulgent Genetics, SCV000894249.1

#	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

From Laboratory of Molecular Genetics and Genomics, Rennes University Hospital, SCV001445849.1

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

Description

Identified in 15 patients harbouring clinical and biochemical symptomes of type 4 haemochromatosis

#	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 DASA, SCV002318955.1

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

Description

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23943237) - PS3_moderate. The c.610G>A;p.(Gly204Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 56158; PMID: 23943237; PMID: 21199650; PMID: 21411349)-PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (FPN1) - PM1. The variant is present at low allele frequencies population databases (rs387907377 – gnomAD 0.00007955%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br.) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic

#	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

Last Updated: Feb 14, 2024

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