We estimate the penetrance of LQTS for KCNQ1 R98H is 13%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. R98H is present in 1 alleles in gnomAD. R98H 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 R98H around 13% (1/11).

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
-1.18	0.992	0	0.678	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	LQT1	Other Disease
LITERATURE, COHORT, AND GNOMAD:	-	1	1	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
98	0	R98H,
97	4
99	4	P99R, P99Q,
96	5	T96R,
100	5
95	7	S95G,
101	7
94	8
102	8
93	8	I93V,
103	8
92	9	S92P,
104	9	T104A, T104I,
91	10	V91L,
105	10
90	11
106	11
89	11	P89T, P89L,
107	11	Q107H, Q107H,
88	12	D88E, D88E,
108	12	G108S,
87	13
109	13	R109C, R109L,
86	13	S86R, S86R, S86R,
110	13	V110I,
85	14
111	14	Y111C,
84	14
112	14
83	15
113	15