We estimate the penetrance of LQTS for KCNQ1 A341V is 82%. This variant was found in a total of 192 carriers in 39 papers or gnomAD, 159 had LQTS. A341V is not present in gnomAD. A341V has been functionally characterized in 4 papers. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A341V around 82% (166/202).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-3.64	1.0	-2	0.931	85

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

PubMed ID	Year	Carriers	Unaffected	LQT1	Other Disease
32893267	2020	15	None	15	None
32470535	2020	1	None	1	None
32443288	2020	2	1	1	None
30878014	2019	1	None	1	None
30758498	2019	35	None	23	None
29622001	2018	1	None	1	None
27041096	2016	10	None	10	None
26496715	2016	3	None	3	None
26063740	2015	3	None	3	None
25634836	2015	32	10	22	None
25585005	2015	None	None	None	None
25087618	2014	168	None	None	None
24705789	2014	None	None	None	None
24363352	2014	2	None	None	None
24218437	2013	1	None	1	None
24217263	2013	23	None	23	None
23153844	2012	24	None	1	None
22949429	2012	1	None	1	None
22095730	2012	None	None	None	None
21854832	2011	None	None	None	None
21063070	None	1	None	1	None
19880070	2009	None	None	None	None
19841300	2009	1	None	1	None
19822806	2009	165	30	135	None
19716085	2009	8	None	8	None
19490272	2009	22	None	22	None
18713323	2008	20	None	None	None
18308161	2008	56	15	41	None
17984373	2007	None	None	None	None
17470695	2007	20	None	20	None
17192539	2006	4	None	4	None
17010804	2006	87	None	43	None
16922724	2006	2	None	2	None
16627448	2006	7	2	3	None
16246960	2005	166	26	131	None
16155735	2005	1	None	1	None
15781747	2005	None	None	None	None
15028050	2004	3	None	3	None
14678125	2003	6	None	6	None
LITERATURE, COHORT, AND GNOMAD:	-	192	33	159
VARIANT FEATURES ALONE:	-	10	3	7	-

Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Peak current is relative to wildtype (100% being no different from wildtype). V_0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID	Cell Type	Peak Current IKs (%WT)	V1/2 Act.	Activation time (%WT)	Deactivation time (%WT)
22095730	CHO	6	60.0	5.591883614	0.28742515
15051636	Oocytes	5	None	None	None
10376919	Oocytes		None	None	None
16246960	CHO		None	None	None

Functional parameters are the same as defined above.

PubMed ID	Cell Type	Peak Current IKs (%WT)	V1/2 Act.	Activation time (%WT)	Deactivation time (%WT)
22095730	CHO	54	30.0	1.490811639	0.409181637
15051636	Oocytes		None	None	None
10376919	Oocytes	50	5.0	1.0	None
16246960	CHO	50	None	None	None

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances. This results from the fact that the functional K_V7.1 channel is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor	Distance (Angstroms)	Variants Observed in Individuals
344	7	A344V, A344E,
341	7	A341V, A341E,
345	9	G345R, G345R, G345A,
343	10	P343S, P343L, P343R,
342	11	L342F, L342P,
348	11
312	11	T312del, T312I,
347	11	L347P, L347R,
338	11	S338F,
337	12
346	12
340	12	F340del, F340L, F340L, F340L, F340S,
311	12	T311A, T311I,
349	13	S349W,
351	14	F351L, F351L, F351L, F351S,
310	14	V310I,
339	14	F339del, F339S,
313	14
336	15	A336S,
350	15	G350V, G350R, G350R, G350W,
262	15	L262P, L262R, L262V,