New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review

Jönsson, Åsa Lina M.; Hilberg, Ole; Simonsen, Ulf; Christensen, Jane Hvarregaard; Bendstrup, Elisabeth

doi:10.1186/s13023-023-02712-7

Orphanet Journal of Rare Diseases

Table 1 Summary of 49 families/68 patients carrying pathogenic variants in SLC34A2 and variant properties

From: New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review

Id	Allele state	Exon	Nucleotide change	Protein change	Localisation in protein^*	Pathogenic in silico predictions^†	Refs
1–6	Hom	1	c.-6773_-6588del	p.?	Involving promoter region and Ex. 1	NA	[5]
7	Hom	2–6	∼ 5.5 kb deletion	p.?	N-terminal to small IC-loop btw. TMDs 4–5	NA	[73]
8–9	Hom	3	c.114delA	p.Asp39IlefsTer7	N-terminal	Yes	[5]
10	Hom	3	c.212_224del	p.Asn71IlefsTer27^‡	N-terminal	NA	[74]
11–16	Hom	3	c.226C>T	p.Gln76Ter	N-terminal	Yes	[5, 35, 75]
17–18	Hom	4	c.316G>C	p.Gly106Arg	TMD 1	Yes	[5, 76]
19	Het Het	4 11	c.316G>A c.1238G>A	p.Gly106Arg p.Trp413Ter	TMD 1 TMD 7	Yes Yes	[3]
20–21	Hom	5	c.380-345_ c.523+659del	p.?	Small EC-loop btw. TMDs 1–2 to part of TMD 3	NA	[86]
22	Het Het	5 Int. 5	c.448G>A c.524-1G>C	p.Gly150Arg p.?	TMD 2 Acceptor-splice site	Yes Yes^††	[94]
23–24	Hom	Int. 5-Ex. 6	c.524-18_559del	p.?	TMDs 3–4	NA	[87, 92]
25	Hom	6	c.560G>A	p.Gly187Glu	TMD 4	Yes	[3]
26–28	Hom	6	c.575C>A	p.Thr192Lys	TMD 4	Yes	[43]
29–31	Hom	6	c.593T>C	p.Ile198Thr	TMD 4	Yes^§	[77, 95]
32	Hom	7	c.646G>T	p.Gly216Ter	Small IC-loop btw. TMDs 4–5^l	Yes	[3]
33–34	Hom	8	c.857_871delins19	p.Ile286LysfsTer29	Large EC-loop	NA	[6]
35	Hom	8	c.893_897delTTGTC	p.Leu298GlnfsTer14	Large EC-loop	NA	[78]
36	Hom	8	c.906G>A	p.Trp302Ter	Large EC-loop	Yes	[3]
37–42	Hom	8	c.910A>T	p.Lys304Ter	Large EC-loop	Yes	[80, 83, 88]
43	Het Het	8 12	c.910A>T c.1363T>C	p.Lys304Ter p.Tyr455His	Large EC-loop Small IC-loop btw. TMDs 8–9	Yes Yes	[81]
44–47	Hom	Int. 9	c.1048+1G>A^**	p.?	Donor-splice site	Yes^††	[6]
48	Het Het	Int. 9 12	c.1048+1G>A c.1390G>C	p.? p.Gly464Arg	Donor-splice site TMD 9	Yes^†† Yes	[79]
49	Hom	10	c.1136G>A	p.Cys379Tyr	TMD 6	Yes	[3]
50	Hom	11	c.1238G>A	p.Trp413Ter	TMD 7	Yes	[3]
51–52	Hom	11	c.1327delC	p.Leu443Ter	TMD 8	Yes	[3]
53–54	Hom	11	c.1328delT	p.Leu443ArgfsTer6	TMD 8	Yes	[5, 89]
55	Hom	Int. 11	c.1333+1G>A	p.?	Donor-splice site	Yes^††	[3]
56	Hom	12	c.1342delG	p.Val448Ter	TMD 8	Yes	[5]
57–58	Hom	12	c.1342_1361del	p.Val448LeufsTer209	TMD 8	NA	[85, 91]
59–60	Hom	12	c.1390G>C	p.Gly464Arg	TMD 9	Yes	[3]
61–63	Hom	12	c.1402_1404delACC	p.Thr468del	TMD 9	Yes	[2, 3]
64	Hom	12	c.1456C>T	p.Gln486Ter	Small EC-loop btw. TMDs 9–10	Yes	[82]
65–66	Hom	13	c.1493G>T	p.Gly498Val	TMD 10	Yes	[93]
67	Hom	13	c.1653_1660del	p.Trp552AlafsTer80^‡‡	Small EC-loop btw. TMDs 11–12	NA	[90]
68	Hom	1–13	Whole gene deletion	NA	NA	NA	[84]

btw. between, Het compound heterozygous, EC extracellular, Hom homozygous, IC intracellular, Id. patient identification, Int. intron, NA not applicable, Ref. reference, TMD transmembrane domain. ^*A model of NaPi-2b was made by superimposing NaPi-2b on rat NaPi-2a predicted topology, modified from Forster et al. 2013 [8] and Virkki et al. 2007 [96] was used to predict the protein locations of the variants (Fig. 6), ^†Variants were predicted to be disease causing, possibly or probably damaging or deleterious by at least one of following: Mutation Taster [97], PANTHER [98], Polyphen-2 [99], PROVEAN [100], and Human Splicing Finder [101]. ^‡Originally reported as p.Asn71IlefsX25 [74], ^§Prediction by PANTHER: "probably benign", ^lAssumed critical area for electrogenicity, ^**Originally reported as IVS8 + 1G>A [6], ^††Prediction by Human Splicing Finder: "alteration of the WT acceptor/donor site, most probably affecting splicing". ^‡‡Originally reported as p.Trp552AlafsTer109 [90]. SLC34A2 DNA ref sequence: Ensembl Transcript ID ENST00000382051.8 (GRCh38.p13 assembly)

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ISSN: 1750-1172

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