TABLE 2

Variants in SLC34A2 identified in the patients

Patient ID	Nucleotide change	Exon	Protein change	Pathogenicity variant class^#	Variant severity^¶	Clinical disease severity⁺	Reference
*Eight novel allelic variants in SLC34A2* identified in PAM patients**
1^§	c.316G>A c.1238G>A	4 11	p.Gly106Arg p.Trp413Ter	I II	Moderate	Mild
2	c.560G>A	6	p.Gly187Glu	III	Moderate	Mild
3	c.646G>T	7	p.Gly216Ter	II	Severe	Severe
4	c.906G>A	8	p.Trp302Ter	II	Moderate	Mild
5	c.1136G>A	10	p.Cys379Tyr	III	Mild	Mild
6	c.1238G>A	11	p.Trp413Ter	II	Moderate	Not applicable
7^ƒ	c.1327delC	11	p.Leu443Ter	II	Severe	Severe^##
8	c.1327delC	11	p.Leu443Ter	II	Severe	Severe
9	c.1333+1G>A	Intron 11	p.?	II	Severe	Moderate
*Two recurrent allelic variants in SLC34A2* identified in PAM patients**
10^¶¶	c.1390G>C	12	p.Gly464Arg	I	Moderate	Mild	[16]⁺⁺
11	c.1390G>C	12	p.Gly464Arg	I	Moderate	Mild	[16]⁺⁺
12	c.1402_1404delACC	12	p.Thr468del	I	Moderate	Severe
13	c.1402_1404delACC	12	p.Thr468del	I	Moderate	Severe	[2]
14	c.1402_1404delACC	12	p.Thr468del	I	Moderate	Moderate	[2]

PAM: pulmonary alveolar microlithiasis. ^#: based on the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria [35] (where I: pathogenic, II: likely pathogenic, III: uncertain significance, IV: likely benign and V: benign); ^¶: predicted effect on NaPi-2b function based on variant type and localisation within the protein. Variants causing premature truncation or with a presumed crucial localisation within the protein scored one point each. Missense variants and small in-frame deletions scored zero points (where mild: 0 points, moderate: 1 point and severe: 2 points); ⁺: disease severity was graded into three groups: mild, moderate and severe, based on a composite measure of the patient's symptoms, lung function, limitation of life due to PAM, signs of advanced disease and disease course (nine parameters in total); ^§: compound heterozygous allele state (all other patients had variants in a homozygous allele state); ^ƒ: sister of patient 8; ^##: deceased; ^¶¶: brother of patient 11; ⁺⁺: Izumi et al. [16] presented the variant c.1390G>C in heterozygous state together with c.1048+1G>A in a PAM patient (SLC34A2 DNA reference sequence: Ensembl Transcript ID ENST00000382051.7 (GRCh38.p12 assembly)).