We estimate the penetrance of LQTS for KCNQ1 R594Q is 75%. This variant was found in a total of 34 carriers in 21 papers or gnomAD, 26 had LQTS. R594Q is present in 7 alleles in gnomAD. R594Q has been functionally characterized in 1 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R594Q around 75% (32/44).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.41	0.999	1	0.846	72

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
34135346	2021	1	None	1	None
33777698	2021	2	None	2	None
32893267	2020	11	None	11	None
30974404	2019	2	1	1	None
30758498	2019	6	None	None	None
29677589	2018	None	None	None	None
27041096	2016	4	None	4	None
26496715	2016	1	None	1	None
26481773	2015	None	None	None	None
24218437	2013	3	None	3	None
23631430	2013	4	None	None	None
23153844	2012	14	None	1	None
22949429	2012	3	None	3	None
22885918	2012	1	None	1	None
21956039	2011	1	None	1	None
19841300	2009	3	None	3	None
19716085	2009	15	None	15	None
17470695	2007	11	None	11	None
16818214	2006	1	None	1	None
14678125	2003	3	None	3	None
11140949	2000	1	None	1	None
LITERATURE, COHORT, AND GNOMAD:	-	34	8	26
VARIANT FEATURES ALONE:	-	10	4	6	-

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)
15051636	Oocytes	5	60.0	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)
15051636	Oocytes	70	0.0	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
594	0	R594Q, R594P,
593	4	N593S,
595	4	V595L, V595L,
592	5
596	5	E596del, E596K,
591	7	R591H, R591C, R591L,
597	7
590	8	A590T,
598	8	K598R,
589	8	G589D, G589S,
599	8
588	9	I588F,
600	9	T600M,
587	10	T587M, T587R,
601	10
586	11	N586D,
602	11
585	11	S585N,
603	11
584	12	G584S,
604	12
583	13	R583H, R583C, R583G,
605	13
582	13
606	13
581	14
607	14	A607T,
580	14	S580G, S580N,
608	14
579	15
609	15