We estimate the penetrance of LQTS for KCNH2 T436M is 3%. This variant was found in a total of 22 carriers in 3 papers or gnomAD (version 4), 0 had LQTS. T436M is present in 20 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 40% of WT with a standard error of 19%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. T436M has been functionally characterized in 2 papers. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T436M around 3% (1/32).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-0.424	0.021	-1	0.559	6

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	LQT2	Other Disease
Italy Cohort	2020	1	1	0
11854117	2002	1	0	1
26129877	2015	1	1		atrial fibrillation
LITERATURE, COHORT, AND GNOMAD:	-	22	11	0	-
VARIANT FEATURES ALONE:	-	10	9	1	-

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.

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V_0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is 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	S.S Peak (%WT)	Peak Tail IKr (%WT)	V1/2 Act.	V1/2 Inact.	Recov. Inact.	Deactivation (%WT)
16432067	HEK293		135	None	None	None	None
26129877	CHO		143	1.4	6.5	None	1.735099338

Functional parameters are the same as defined above.

PubMed ID	Cell Type	S.S Peak (%WT)	Peak Tail IKr (%WT)	V1/2 Act.	V1/2 Inact.	Deactivation (%WT)
16432067	HEK293			None	None	None
26129877	CHO			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 since the functional K_V11.1 channel (protein product of KCNH2/hERG) 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
436	0	T436M,
435	4	E435X, E435G,
437	4
434	5
438	5	E438K, E438X,
433	7
439	7
432	8
440	8	P440L,
431	8	F431L, F431L, F431L,
441	8	P441L, P441R,
430	9
442	9
429	10	A429P, A429V,
443	10	T443fsX, T443N,
428	11	S428L, S428fsX, S428X,
444	11	E444D, E444D, E444K,
427	11	Y427S, Y427C, Y427H,
445	11
426	12	P426H,
446	12
425	13
447	13	Y447X,
424	13
448	13	A448T, A448S,
423	14
449	14
422	14	A422T,
450	14
421	15	T421fsX, T421M,
451	15	P451L,