We estimate the penetrance of LQTS for KCNQ1 V254M is 92%. This variant was found in a total of 125 carriers in 21 papers or gnomAD, 117 had LQTS. V254M is not present in gnomAD. V254M has been functionally characterized in 3 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 V254M around 92% (123/135).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-2.92	1.0	0	0.918	80

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	25	None	25	None
31520628	2019	1	None	1	2 miscarriage
30758498	2019	28	None	22	None
29439887	2018	19	6	13	None
27041096	2016	1	None	1	None
26496715	2016	2	None	2	None
24667783	2015	3	None	3	None
24606995	2014	1	None	1	None
24363352	2014	2	None	None	None
24217263	2013	1	None	1	None
23631430	2013	3	None	None	None
23153844	2012	118	None	1	None
22949429	2012	2	None	2	None
19841300	2009	2	None	2	None
19716085	2009	10	None	10	None
19490272	2009	62	None	62	None
17470695	2007	59	None	59	None
17192539	2006	4	None	4	None
14756674	2004	7	None	7	None
14678125	2003	70	None	70	None
12820704	2003	4	2	2	None
LITERATURE, COHORT, AND GNOMAD:	-	125	8	117
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)
22456477	HEK		None	None	None
14756674	Xeno	7	41.5	None	None
10376919	Oocytes		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)
22456477	HEK	30	None	None	None
14756674	Xeno	25	39.8	None	None
10376919	Oocytes	30	13.0	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
261	10	E261K, E261D, E261D, E261G, E261Q,
249	10	R249S, R249S,
355	11
250	11	L250H, L250P,
251	11	L251P, L251Q,
262	12	L262P, L262R, L262V,
260	12
265	12	T265I,
257	13	I257V,
258	13	H258P, H258N, H258R, H258Y,
264	13
358	13	K358T,
248	13	W248C, W248C, W248R, W248R,
255	13
254	14	V254M, V254L, V254L,
346	14
245	14	G245V,
259	14	R259C, R259H, R259L, R259G,
349	14	S349W,
263	14
345	14	G345R, G345R, G345A,
342	14	L342F, L342P,
351	14	F351L, F351L, F351L, F351S,
339	14	F339del, F339S,
359	15	Q359del,