SCN5A Variant L173Q Detail

We estimate the penetrance of LQTS for SCN5A L173Q around 4% and the Brugada syndrome penetrance around 29%. SCN5A L173Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L173Q is not present in gnomAD. L173Q has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (2 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L173Q around 4% (0/10) and the Brugada syndrome penetrance around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.907 37 0
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 BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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.

L173Q has 43 previously observed neighbors within 15 angstroms

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. 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
121 11 R121W, R121Q,
198 10
124 9 A124D,
114 12
170 6 F170I,
184 13 H184R,
171 7
137 13 I137V,
197 13
113 15 V113I, V113A,
129 15
169 7
177 5 L177P,
189 15
123 12 A123G, A123V,
127 11
125 11 V125L,
174 5 V174I,
133 12
182 14 C182R, C182Y,
134 15 N134S,
205 13 c.612-2A>G, Y205X,
166 11 A166T,
179 11 R179X, R179Q,
172 5
185 12 A185V, A185T,
165 13
180 10 G180V,
120 11
126 15 K126E,
168 11
175 7 K175N,
202 13 I202T,
194 14
188 11
167 11
178 9 A178G,
128 10 c.381dupT,
201 12
118 14
181 11
176 6
173 0