. Author manuscript; available in PMC: 2021 Jun 1.

Published in final edited form as: Acta Neuropathol. 2020 Mar 31;139(6):1089–1104. doi: 10.1007/s00401-020-02150-w

Table 1: Genetic data of individuals included in this study.

RYR1 sequencing methods. Mode of inheritance (MOI) determined through pedigree data. For cases without parental genetic testing, a plausible mode of inheritance was established through careful evaluation of clinical manifestations. ClinVar clinical significance as reported at https://www.ncbi.nlm.nih.gov/clinvar. Structure-based variant pathogenicity assignment provided in arbitrary units (AU) and as the probability of pathogenicity as described.

Case	Sex	MOI	RYR1 sequencing	Nucleotide change	Amino acid change	Variant classification (based on ClinVar)	Structure-based variant pathogenicity assignment		Protein Location
Case	Sex	MOI	RYR1 sequencing	Nucleotide change	Amino acid change	Variant classification (based on ClinVar)	Score (AU)	Pathogenicity probability	Protein Location
1	M	Recessive	Complete	c.4999C>T	p.Arg1667Cys	Conflicting	0.000	0.682	Jsol
				c.5140_5142del	p.Leu1714del	VUS	-	-	Jsol
				c.14126C>T	p.Thr4709Met	Pathogenic	0.001	0.686	pVSD (S2S3)
2	M	Dominant	Complete	c.12553G>A	p.Ala4185Thr	Conflicting	0.001	0.685	TaF
3	F	Dominant	Targeted	c.7354C>T	p.Arg2452Trp	Pathogenic	0.189	0.973	BSol
4	F	De novo	Complete	c.14693T>C	p.Ile4898Thr	VUS	0.280	0.993	Pore
5	F	Dominant	Targeted	c.14818G>A	p.Ala4940Thr	Pathogenic	0.159	0.958	Pore (S6c)
6	F	Dominant	Targeted	c.14582G>A	p.Arg4861His	Pathogenic	0.195	0.975	Pore
7	M	Recessive	Complete	c.6721C>T	p.Arg2241^*	Pathogenic	-	-	Bsol
				c.325C>T	p.Arg109Trp	Pathogenic	0.081	0.878	NTD-A
				c.2122G>A	p.Asp708Asn	Conflicting	0.000	0.682	SPRY1
				c.1453A>G	p.Met485Val	Conflicting	0.000	0.684	Nsol
8	F	Dominant ^a	Complete	c.14582G>A	p.Arg4861His	Pathogenic	0.195	0.975	Pore
8	F	Dominant ^a	Complete	c.13331_13351dup	p. Gly4444–50dup	VUS	-	-	Unresolved
9	M	Dominant	Targeted	c.12083C>T	p.Ser4028Leu	VUS	0.091	0.893	Csol
10	F	Dominant	Targeted	c.14558C>T	p.Thr4853Ile	Pathogenic	0.179	0.969	Pore
11	F	Dominant	Exome	c.14731G>A	p.Glu4911Lys	VUS	0.096	0.900	Pore
12	M	Recessive	Exome	c.1589G>A	p.Arg530His	VUS	0.161	0.959	Nsol
				c.3127C>T	p.Arg1043Cys	VUS	0.001	0.685	RY1&2
				c.7007G>A	p.Arg2336His	Pathogenic	0.155	0.956	Bsol
13	M	Dominant	Targeted	c.14681C>A	p.Ala4894Asp	VUS	0.269	0.992	Pore
14	M	Recessive	Complete	c.1993del	p.Val665^*	Likely pathogenic	-	-	SPRY1
14	M	Recessive	Complete	c.4816C>A	p.Arg1606Ser	VUS	0.001	0.686	SPRY3
15	M	De novo	Exome	c.12083C>T	p.Ser4028Leu	VUS	0.091	0.893	Csol
16	M	Dominant	Complete	c.14209C>T	p.Arg4737Trp	Pathogenic	0.174	0.966	pVSD (S2S3)
17	M	Recessive	Targeted	c.10097G>A	p.Arg3366His	VUS	0.109	0.916	Bsol
				c.11798A>G	p.Tyr3933Cys	VUS	0.002	0.689	Csol
				c.14645C>T	p.Thr4882Met	Conflicting	0.018	0.736	Pore

Abbreviations: M, male; F, female; MOI, mode of inheritance; VUS, variant of uncertain significance; del, deletion

premature stop codon; Jsol, junctional solenoid; pVSD, pseudo-voltage-sensing domain; S2S3, Helical-bundle domain between S2 and S3; TaF, Thumb and Forefingers domain; Bsol, bridging solenoid; Pore, channel pore domain; S6c, Cytoplasmic extension of S6; NTD-A, N-terminal domain A; SPRY1, SP1a / Ryanodine receptor domain 1; Nsol, N-terminal solenoid; Csol, core solenoid; RY1&2, RYR Repeats 1 and 2; SPRY3, SP1a / Ryanodine receptor domain.