We estimate the penetrance of LQTS for KCNQ1 S92P is 8%. This variant was found in a total of 5 carriers in 0 papers or gnomAD, 0 had LQTS. S92P is present in 5 alleles in gnomAD. S92P has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S92P around 8% (1/15).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-1.75	0.049	-1	0.594	4

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
LITERATURE, COHORT, AND GNOMAD:	-	5	5	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.

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
92	0	S92P,
91	4	V91L,
93	4	I93V,
90	5
94	5
89	7	P89T, P89L,
95	7	S95G,
88	8	D88E, D88E,
96	8	T96R,
87	8
97	8
86	9	S86R, S86R, S86R,
98	9	R98H,
85	10
99	10	P99R, P99Q,
84	11
100	11
83	11
101	11
82	12
102	12
81	13	P81L,
103	13
80	13
104	13	T104A, T104I,
79	14
105	14
78	14	D78H,
106	14
77	15	S77F,
107	15	Q107H, Q107H,