We estimate the penetrance of LQTS for KCNH2 Y447X is %. This variant was found in a total of 24 carriers in 2 papers or gnomAD, 1 had LQTS. Y447X is present in 22 alleles in gnomAD. Y447X has not been functionally characterized. This residue is located in a None region for LQT2.

PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density (%)
None	None	None	None

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
12402336	2002	1	0	1
LITERATURE, COHORT, AND GNOMAD:	-	24	23	1	-
VARIANT FEATURES ALONE:	-	10	NA	NA	-

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.