Table IV.

Predicted functional consequence of somatic mutations in LGI1.

IDa	Predicted protein	Allowed in orthologsb	Allowed in paralogsc	Notes	Finald
78	I122K	I	I	Highly conserved in paralogs. Hydrophobic residues can be found in all leucine repeat-rich proteins with L present in all except in this second repeat of LGI1 (I). This change from a hydrophobic to a positively charged amino acid at this position is likely to impact function.	FD
73	N125S	N	N	Located in the leucine-rich repeat. N is completely conserved in LGI1 orthologs, paralogs, and other leucine repeat-rich proteins (Slit, Toll, Osteomodulin, Tartan, Biglycan, ALS, lumican, PGPIX and Chondroadherin) (6) suggesting an important function.	FD
194	K128E	K	E, W, G	Conserved in orthologs but highly variable stretch in paralogs. Part of the leucine repeat-rich region but this position is highly variable in other LRR proteins, with D, Q, T, S, E and R being found.	UN
118215	H143R	H	H	Highly conserved in paralogs and is part of the leucine repeat-rich region but this position is highly variable in other LRR proteins, with K, Y, S, D, E and Q being found.	FB
73	L144S	L	L	Highly conserved in paralogs. Hydrophobic residues can be found in all leucine repeat-rich proteins with L present in all except PGPIX (T) and Lumican (I) (6). Located at the splicing junction.	FD
78	K207R	K	K, Q, S	Conservative change in a region that is variable in the paralogs. Located in the cysteine cluster of the LRR flanking region but position is highly variable.	FB
193	C221W	C	C	Conserved C in LRR proteins located at the cysteine cluster of the LRR flanking region, probably important for function.	FD
78	I223T	I	I, T, A	Replacement is allowed in paralogs and is a relatively conservative change.	FB
193	I340V	I	I, L	Conservative change in a conserved position in orthologs and paralogs.	FB
194	Q488X	n/a	n/a	Stop codon that truncates the extreme C-terminus. Notably, frameshifts on codons 440 and 547 have been shown to be deleterious in autosomal-dominant partial epilepsy with auditory features, suggesting that the extreme C-terminus is important for function (28,29).	FD
73	N531D	N	N, D, G, A	Conserved in orthologs but highly variable stretch in paralogs which may suggest a role in conferring specificity.	UN
78	N534I	N	N,D, Q, R	Conserved in orthologs but highly variable stretch in paralogs which may suggest a role in conferring specificity.

^aPatient identity.

^bAmino acids that are found at the corresponding position in the multiple sequence alignment using the homologs as described in Materials and methods.

^cAmino acids that are found at the corresponding position in paralogs LGI1-4 (34), (accession numbers for LGI2-LGI4: AF467954-AF467956).

^dTentative classification of whether the variant is likely to contribute or not to the tumor phenotype: FB, favor benign (or inconsequential, ‘passenger’); FD, favor deleterious (or consequential, ‘driver’) and UN, unknown or not enough information to propose a classification.