. 2021 Nov 4;12:756415. doi: 10.3389/fphar.2021.756415

TABLE 1.

PDVs in the pore domain and their contacts ^a .

PDVs		Contacts
Variant ^b	Syndrome ^c ^, ^d	Variant	Syndrome ^d	Significance	^e	^f
^IS5A²⁴²T	A	^IS6Q⁴¹⁹P	BrS1, NP	VUS		S
V	HCM	^IS6Q⁴¹⁹P	BrS1, NP	VUS		S
^IS5L²⁵⁰V	BrS1	^IS6V⁴¹¹M	LQT3, BrS1, CVP	P		S
^IS5S²⁶²G	A, BrS1	^IP1F³⁵⁸S	NS	VUS		S
^IS5V²⁶³I	Multi	^IVS4I¹⁶³³V	BrS1	VUS		S
^IS5-P1G²⁷⁴S	BrS1	^IS5-P1D³⁵⁶Y	BrS1	LP
^IS5-P1G²⁷⁴S	BrS1	N	NP/BrS1	P/LP
^IS6A⁴¹³E	LQT3	^IIS6L⁹³⁵P	BrS1	NP		S
S	NS
T	A, LQT3,BrS1
^IIS5G⁸⁵⁷D	A, BrS1	^IIS5-P1M⁸⁸¹I	LQT3	VUS	1
^IIS5-P1M⁸⁸¹I	LQT3	^IIS6F⁹¹⁹S	NS	LP	1
^IIS5-P1M⁸⁸¹I	LQT3	^IIS5G⁸⁵⁷D	A, BrS1	VUS	1
^IIP1F⁸⁹²L	CVP	^IVS6V¹⁴⁵¹D	BrS1	VUS	2
I	BrS1	L	NS, A	VUS	2
^IIP1R⁸⁹³H	BrS1^1,3,4,8–10	^IIP2E⁹⁰¹K	BrS1	VUS	2	S
C	BrS1	^IIP2E⁹⁰¹K	BrS1	VUS
^IIIS5V¹³²⁴I	A, BrS1, NP	^IIS3W¹²⁷¹C	BrS1	NP
^IIIS5L¹³⁴²F	BrS1	^IIIP1Y¹⁴⁰⁹C	BrS1	NP		S
^IIIP1L¹⁴¹⁰P	NP	^IIIS5-P2V¹⁴⁰⁰G	CVP	VUS
^IIIP2I¹⁴²⁴F	NP	^IIIS5-P1F¹³⁶°C	BrS1	NP
^IIIP2I¹⁴²⁴F	NP	^IIIS5-P1V¹⁴⁰⁰G	CVP	VUS
^IIIS6V¹⁴⁵¹D	BrS1^1,3	^IIP1F⁸⁹²L	CVP	VUS
L	A, NS	I	BrS1	NP
^IIIS6N¹⁴⁶³K	NP	^IIS6F⁹³⁴S	BrS1	VUS
^IIIS6F¹⁴⁶⁵L	LQT3	^IIIS5V¹³³⁷I	A	VUS		S
		^IIIS5I¹³³⁴V	LQT3, BrS1, NP	CIP		S
		^IVS6F¹⁷⁶°C	BrS1	P		S
		^IVS6L¹⁷⁶¹F	LQT3	NP		S
		H	LQT3	NP		S
^IIIS6I¹⁴⁶⁶T	NP, A	^IIS6F⁹³⁴S	BrS1	VUS		S
V	NP	^IVS6V¹⁷⁶⁴F	BrS1	NP		S
V	NP	^IVS6F¹⁷⁶°C	BrS1	P		S
^IIIS6V¹⁴⁶⁸A	A, BrS1,NP	^IIIS5S¹³³³Y	LQT3	NP		S
^IIIS6V¹⁴⁶⁸A	A, BrS1,NP	^IIIS5V¹³³⁷I	A	VUS		S
^IIIS6I¹⁴⁶⁹F	NP	^IIIS5I¹³³⁴V	LQT3, BrS1, NP	CIP		S
		^IVS6L¹⁷⁶¹F	LQT3	NP		S
		H	LQT3	NP		S
		^IVS6V¹⁷⁶⁴F	BrS1	NP		S
^IVS5V¹⁶⁶⁷L	NP	^IVS6I¹⁷⁵⁸V	A, BrS1	VUS
^IVS5-P1D¹⁶⁹⁰N	A, BrS1, NS^14,15,16	^IP2R³⁸³K	BrS1	VUS
^IVP1M¹⁷⁰¹I	BrS1, DCM¹⁷	^IVS5M¹⁶⁶⁸T	A	VUS
		^IS6M³⁹⁰I	A	VUS
		V	BrS1, A	VUS
		^IS6M³⁹⁴I	A	VUS
		L	A	VUS
^IVS5I¹⁶⁶⁰V	NP, CVP, BrS1, LQT3^1,3,13,14	^IVS6V¹⁷⁶⁴F	BrS1	NP	3	S
		^IVS6L¹⁷⁶¹F	LQT3	NP		S
		H	LQT3	NP		S
		^IIIS4-S5V¹³²³G	BrS1	NP		S
		I	A, BrS1	VUS		S
		^IVS6M¹⁷⁶⁶I	CVP, BrS1	VUS		S
		K	NP, BrS1, SSS	VUS
		V	BrS1	VUS
		T	HCM	VUS
		L	LQT3	P
		^IIIS6−IVS1F¹⁴⁸⁶L	SIDS	NP
^IVP1L¹⁷⁰⁴H	BrS1	^IVS5M¹⁶⁶⁸T	A	VUS
^IVP1T¹⁷⁰⁹M	A, BrS1,CVP,NP^1,3,18	^IIIP1-P2K¹⁴¹⁹E	BrS1	NP
		^IP1-P2W³⁷⁴G	BrS1	NP
		^IP1-P2Q³⁷¹R	BrS1	VUS
		^IS6I³⁹⁷T	BrS1, LQT3, NP	CIP
^IVS6M¹⁷⁶⁶I	BrS1, CVP	^IS6N⁴⁰⁶K	LQT3	P, LP	3	S
K	NP, BrS1, SSS	^IS6N⁴⁰⁶S	BrS1	NP
V	BrS1	^IVS5I¹⁶⁶⁰V	A, BrS1, CVP, LQT3	CIP
T	HCM
L	LQT3

See Energy Calculations and Optimization Section for definition of contacts.

All PDVs were listed as VUS in ClinVar-2019. In ClinVar-2021, conflicting interpretations of pathogenicity is reported for three variants (R⁸⁹⁴H, G¹²⁶²D, I¹⁶⁶⁰V) and two variants (D¹⁹⁷G, L²²⁵V) are classified as likely pathogenic.

Superscripted numbers refer to clinical and experimental studies of the variants. 1. Huang et al. (2017), 2. Ortiz-Bonnin et al. (2016), 3. Kapplinger et al. (2010), 4. Walsh et al. (2014), 5. Calloe et al. (2013), 6. Liang et al. (2016), 7. Son et al. (2018), 8. Zakliaz’minskaia et al. (2013), 9. Kapplinger et al. (2015), 10. Rudic et al. (2016), 11. Shin et al. (2004), 12. Priganc et al. (2017), 13. Cordeiro et al. (2006), 14. Selga et al. (2015), 15. Núñez et al. (2013), 16. Zeng et al. (2016), 17. Bodian et al. (2017), 18. Li et al. (2018), 19. Brewer et al. (2020).

Abbreviations: A, Arrhythmia; AF, atrial fibrillation; BrS1, Brugada syndrome; CA, Cardiac Arrest; CIP, Conflicting interpretations of pathogenicity; CVP, Cardiovascular phenotype; DCM, Dilated cardiomyopathy; HCM, Hypertrophic cardiomyopathy; LP, Likely Pathogenic, LQT3, Long QT syndrome Type 3; M, Multiple diseases; NP, not provided; NR, Variants are not reported in ClinVar; NS, Not Specified; P, Pathogenic; PFHB-1, Progressive Familial Heart Block type 1A; PFVF1, Paroxysmal Familial Ventricular Fibrillation 1; SIDS, Sudden Infant Death Syndrome; VUS, Variant of Uncertain Significance.

Matching numbers show WT residues that are in contact in the cryo-EM structure.

state-dependent contacts involving residues that move upon activation gating (located C-terminal to gating-hinge in KcsA).