We estimate the penetrance of LQTS for KCNQ1 T587M is 80%. This variant was found in a total of 22 carriers in 20 papers or gnomAD, 20 had LQTS. T587M is not present in gnomAD. T587M 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T587M around 80% (25/32).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-3.74	0.976	-2	0.831	67

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
30758498	2019	39	None	20	None
30591322	2019	None	None	None	None
30369311	2018	1	None	1	None
29688407	2018	1	1	None	None
26496715	2016	1	None	1	None
24217263	2013	1	None	1	None
23631430	2013	1	None	None	None
22949429	2012	1	None	1	None
22677073	2012	1	None	None	SUDS
20487114	2010	2	1	1	None
20348026	2010	None	None	None	None
19959132	2009	None	None	None	None
19841300	2009	1	None	1	None
19716085	2009	2	None	2	None
18752142	2008	13	None	1	RWS
18595190	2008	1	None	None	None
17192539	2006	1	None	1	None
11162126	2001	3	None	3	None
9799083	1998	1	None	1	None
LITERATURE, COHORT, AND GNOMAD:	-	22	2	20
VARIANT FEATURES ALONE:	-	10	5	5	-

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)
19959132	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)
19959132	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
587	0	T587M, T587R,
586	4	N586D,
588	4	I588F,
585	5	S585N,
589	5	G589D, G589S,
584	7	G584S,
590	7	A590T,
583	8	R583H, R583C, R583G,
591	8	R591H, R591C, R591L,
582	8
592	8
581	9
593	9	N593S,
580	10	S580G, S580N,
594	10	R594Q, R594P,
579	11
595	11	V595L, V595L,
578	11	E578K, E578V,
596	11	E596del, E596K,
577	12
597	12
576	13	V576I,
598	13	K598R,
575	13
599	13
574	14	I574V,
600	14	T600M,
573	14	F573L, F573L, F573L,
601	14
572	15
602	15