The Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease)

Table 1

Comprehensive list of published SCL40A1 variants.

Exon	Nucleotide change	Amino acid change	Localization in protein	Index cases (=) (PMID)	Functional classification		ACMG/AMP classification	Diagnosis
					In vitro findings (PMID)	Structural predictions (this study)
3	c.190T>A	p.Tyr64Asn	TM2	1 (12857562)	Gain-of-function (15831700, 15692071, 19709084, 19383972, and 23943237)		Pathogenic	Hemochromatosis type 4
3	c.190T>C	p.Tyr64His	TM2	1 (25396007)		Deleterious	Likely pathogenic	Hemochromatosis type 4
3	c.205G>A	p.Ala69Thr	TM2	2 (27177411, 29154924)	Gain-of-function (24859227, 29154924)		Likely pathogenic	Hemochromatosis type 4
3	c.214G>T	p.Val72Phe	TM2	1 (18177470)	Gain-of-function (29237594)		Likely pathogenic	Hemochromatosis type 4
3	c.230C>A	p.Ala77Asp	TM2	3 (10471458, 15951560, and 18160317)	Loss-of-function (15831700, 15692071, 16885049, 23943237, 19846751, 15935710, 23784628, 21396368, 24714983, 24859227, 30002125, and 32450003)		Pathogenic	Ferroportin disease
3	c.238G>A	p.Gly80Ser	TM2	12 (16135412, 16885049, 17052926, 18420432, 21094556, 24370385, and 24714983)	Loss-of-function (21094556, 24714983, and 16885049)		Pathogenic	Ferroportin disease
3	c.239G>T	p.Gly80Val	TM2	1 (16351644)		Deleterious	Likely pathogenic	Ferroportin disease
3	c.252C>G	p.Asp84Glu	TM2	1 (28681497)	Loss-of-function (28681497)		Likely pathogenic	Ferroportin disease
3	c.262A>G	p.Arg88Gly	TM3	3 (17951290, 24714983)	Loss-of-function (23943237, 24714983)		Likely pathogenic	Ferroportin disease
3	c.263G>C	p.Arg88Thr	TM3	1 (16257244)		Deleterious	Pathogenic	Ferroportin disease
3	c.263G>T	p.Arg88Ile	TM3	1 (33385755)		Deleterious	Pathogenic	Ferroportin disease
4	c.386T>C	p.Leu129Pro	TM4	1 (24644245)			VUS	Unexplained hyperferritinemia
5	c.430A>C	p.Asn144His	TM4	1 (11431687)	Gain-of-function (15831700, 15692071, 15956209, 19846751, 15935710, 23784628, 24859227, 19937651, and 30002125)		Pathogenic	Hemochromatosis type 4
5	c.430A>G	p.Asn144Asp	TM4	1 (15030991)	Gain-of-function (15692071, 19383972, and 29237594)		Pathogenic	Hemochromatosis type 4
5	c.431A>C	p.Asn144Thr	TM4	1 (12865285)	Gain-of-function (19383972, 19846751)		Pathogenic	Hemochromatosis type 4
5	c.431A>G	p.Asn144Ser	TM4	1 (18403150)		Deleterious	Likely pathogenic	Hemochromatosis type 4
5	c.454A>T	p.Ile152Phe	TM4	1 (18713659)	Loss-of-function (23784628, 18713659)		Likely pathogenic	Ferroportin disease
5	c.469G>T	p.Asp157Tyr	TM4	1 (24714983)	Loss-of-function (24714983)		Pathogenic	Ferroportin disease
5	c.470A>G	p.Asp157Gly	TM4	3 (12730114, 24714983)	Loss-of-function (15935710, 15956209, 16457665, and 24714983)		Likely pathogenic	Ferroportin disease
5	c.469G>A	p.Asp157Asn	TM4	2 (18177470, 29154924)		Deleterious	Likely pathogenic	Ferroportin disease
5	c.470A>C	p.Asp157Ala	TM4	3 (20230395, 20533066, and 26183747)		Deleterious	Likely pathogenic	Ferroportin disease
5	c.474G>T; c.474G>C	p.Trp158Cys	TM4	2 (21396368, 28110135)	Loss-of-function (21396368)		Pathogenic	Ferroportin disease
5	c.479T>C	p.Val160Ala	TM4	1 (34828384)			VUS	Unexplained hyperferritinemia
5	c.484_486del	p.Val162del	TM4	20 (12091366, 12091367, 12123233, 12406098, 15671438, 15753550, 15986403, 17052926, 17997113, 18160317, 24714983, 25742196, 25744502, 29154924, and 31689754)	Loss-of-function (15692071, 15935710, 15956209, 17729390, 28681497, 19846751, 16457665, and 24714983)		Pathogenic	Ferroportin disease
6	c.521A>T	p.Asn174Ile	TM5	3 (16135412, 16885049)	Loss-of-function (24767627, 23784628, 16885049, and 29154924)		Likely pathogenic	Ferroportin disease
6	c.533G>A	p.Arg178Gln	TM5	9 (17997113, 17951290, 30002125, and 32450003)	Loss-of-function (30002125, 32450003)		Pathogenic	Ferroportin disease
6	c.536G>C	p.Arg179Thr	TM5	1 (34828384)			VUS	Unexplained hyperferritinemia
6	c.539T>C	p.Ile180Thr	TM5	3 (16257244, 22890139, and 24714983)	Neutral (24714983)		Likely benign	Unexplained hyperferritinemia
6	c.541G>A	p.Asp181Asn	TM5	1 (29154924)	Loss-of-function (29154924)		Pathogenic	Ferroportin disease
6	c.542A>T	p.Asp181Val	TM5	4 (16351644, 24714983, and 24859227)	Loss-of-function (24767627, 24859227, and 24714983)		Pathogenic	Ferroportin disease
6	c.546G>T	p.Gln182His	TM5	1 (12730114)	Gain-of-function (15935710, 15956209, and 16457665)		Likely pathogenic	Hemochromatosis type 4
6	c.553A>G	p.Asn185Asp	TM5	2 (16111902, 21199650)	Loss-of-function (23943237)		Pathogenic	Ferroportin disease
6	c.610G>C	p.Gly204Arg	TM6	1 (29154924)	Gain-of-function (29154924)		Pathogenic	Hemochromatosis type 4
6	c.610G>A	p.Gly204Ser	TM6	2 (21199650, 21411349)	Gain-of-function (23943237, 29237594)		Pathogenic	Hemochromatosis type 4
6	c.626C>T	p.Ser209Leu	TM6	2 (27896572, 28110135)			VUS	Unexplained hyperferritinemia
6	c.689C>A	p.Thr230Asn	IC3	1 (24714983)	Neutral (24714983)		Likely benign	Unexplained hyperferritinemia
6	c.698T>C	p.Leu233Pro	IC3	2 (18713659, 24714983)	Loss-of-function (18713659, 24714983)		Likely pathogenic	Ferroportin disease
6	c.697C>G	p.Leu233Val	IC3	2 (32360131)		Deleterious	Likely pathogenic	Ferroportin disease
6	c.718A>G	p.Lys240Glu	IC3	1 (21175851)	Gain-of-function (22682227)		Likely pathogenic	Hemochromatosis type 4
6	c.744G>T	p.Gln248His	IC3	4 (14636642, 14636644, and 24714983)	Neutral (15692071, 15831700, 23065513, and 24714983)		Benign	Unexplained hyperferritinemia
7	c.797T>C	p.Met266Thr	IC3	1 (24714983)	Neutral (24714983)		Likely benign	Unexplained hyperferritinemia
7	c.809A>T	p.Asp270Val	IC3	2 (15338274, 22584997)	Gain-of-function (29237594)		Likely pathogenic	Hemochromatosis type 4
7	C.887G>A	p.Arg296Gln	IC3	1 (29154924)	Loss-of-function (29154924)		Likely pathogenic	Ferroportin disease
7	c.968G>T	p.Gly323Val	TM7	1 (12730114)	Loss-of-function (15935710, 15956209, and 16457665)		Likely pathogenic	Ferroportin disease
7	c.977G>C	p.Cys326Ser	TM7	1 (15727899)	Gain-of-function (29237594, 19383972)		Pathogenic	Hemochromatosis type 4
7	c.977G>A	p.Cys326Tyr	TM7	1 (19342478)	Gain-of-function (15692071, 15831700, 23784628, 19937651, 30002125, 32450003, 23065513, 21396368, 24859227, 28681497, and 24714983)		Pathogenic	Hemochromatosis type 4
7	c.977G>T	p.Cys326Phe	TM7	1 (26059880)		Deleterious	Likely pathogenic	Hemochromatosis type 4
7	c.997T>C	p.Tyr333His	TM7	3 (30500107)	Gain-of-function (30500107)		Likely pathogenic	Hemochromatosis type 4
7	c.1014T>G	p.Ser338Arg	TM8	1 (17383046)	Gain-of-function (17383046, 19846751, and 29237594)		Pathogenic	Hemochromatosis type 4
7	c.1035G>C	p.Leu345Phe	TM8	1 (24714983)	Neutral (24714983)		Likely benign	Unexplained hyperferritinemia
7	c.1049C>A	p.Ala350Asp	TM8	1 (34828384)			VUS	Unexplained hyperferritinemia
7	c.1051A>G	p.Ile351Val	TM8	1 (24714983)	Neutral (24714983)		Likely benign	Unexplained hyperferritinemia
7	c.1328C>T	p.Pro443Leu	EC5	1 (24714983)	Neutral (24714983)		Benign	Unexplained hyperferritinemia
7	c.1402G>A	p.Gly468Ser	TM10	1 (18160816)	Loss-of-function (splicing defect) (33341511)		Likely pathogenic	Ferroportin disease
8	c.1467A>C	p.Arg489Ser	TM11	1 (16258219)		Deleterious	Likely pathogenic	Ferroportin disease
8	c.1466G>A	p.Arg489Lys	TM11	1 (19937651)	Loss-of-function (19937651)		Pathogenic	Ferroportin disease
8	c.1468G>A	p.Gly490Ser	TM11	3 (17951290, 24714983)	Loss-of-function (24714983)		Pathogenic	Ferroportin disease
8	c.1469G>A	p.Gly490Asp	TM11	9 (12873829, 24714983)	Loss-of-function (15692071, 15956209, and 24714983)		Likely pathogenic	Ferroportin disease
8	c.1481G>A	p.Gly494Asp	TM11	1 (34828384)		Deleterious	Likely pathogenic	Ferroportin disease
8	c.1502A>G	p.Tyr501Cys	TM11	1 (19709084)	Gain-of-function (19709084, 24767627, and 29237594)		Likely pathogenic	Hemochromatosis type 4
8	c.1510G>A	p.Asp504Asn	TM11	1 (24714983)	Gain-of-function (24714983, 29237594)		Likely pathogenic	Hemochromatosis type 4
8	c.1520A>G	p.His507Arg	TM11	3 (21396368, 27629970, and 33673803)	Gain-of-function (21396368, 29237594)		Likely pathogenic	Hemochromatosis type 4
8	c.1531G>A	p.Val511Ile	TM11	1 (30500107)			VUS	Unexplained hyperferritinemia
8	c.1592T>C	p.Val531Ala	TM11	1 (34828384)			VUS	Unexplained hyperferritinemia
8	c.1681A>G	p.Arg561Gly	C-ter	2 (19066423, 24714983)	Neutral (24714983)		Benign	Unexplained hyperferritinemia

SLC40A1 variants are documented based on GenBank accession number NM_014585.5. This table does not include three noncoding variations (c.-181A>G, c.-428-427GG>TT, and c.-59-45del) whose functional impact is unknown and nine missense variations (p.Ala45Glu, p.Ala69Val, p.Ser71Phe, p.Trp158Leu, p.Asn185Thr, p.Ala232Asp, p.Gly267Asp, p.Arg371TRp, and p.Arg371Gln) due to the lack of individual phenotypic information ([71]; [72]; [73]; [21]; [74]). Given our predictions in the context of the SLC40A1 3D structure (pdb 6WBV; Figure 3), we propose to use the supporting evidence code PP5 for the p.Gly494Asp variant and classify it in class 4 (instead of class 3); all other variants discussed in Section 2.3 are rated as class 4 or class 5 regardless of the PP5 criteria.