SCN5A Variant K175N Detail

We estimate the penetrance of LQTS for SCN5A K175N around 1% and the Brugada syndrome penetrance around 48%. SCN5A K175N was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. K175N is not present in gnomAD. K175N has been functionally characterized in 2 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 (4 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 K175N around 1% (0/11) and the Brugada syndrome penetrance around 48% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.8 0.993 -4.94 0.796 76 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
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 0 4 - -
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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 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.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
32533946 2020 HEK 118 7.3 -9.1
20129283 2010

K175N has 59 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 7
124 9 A124D,
131 14
193 13 W193X, W193R,
195 13
130 13
114 13
170 9 F170I,
184 11 H184R,
228 12 K228R,
138 13 M138I,
183 15
171 5
137 10 I137V,
197 8
129 10
196 12
169 10
177 8 L177P,
189 12
123 13 A123G, A123V,
127 10
125 9 V125L,
174 5 V174I,
133 9
182 14 C182Y, C182R,
132 15 c.393-5C>A,
191 11
134 10 N134S,
166 14 A166T,
179 7 R179Q, R179X,
172 5
185 10 A185V, A185T,
199 13 S199T,
165 14
180 9 G180V,
120 15
192 14
126 13 K126E,
136 14 L136P,
168 11
175 0 K175N,
202 14 I202T,
194 8
141 14 I141V, I141N,
188 7
167 12
178 7 A178G,
128 6 c.381dupT,
201 11
225 12 R225Q, R225W,
181 13
176 6
186 15
173 7
200 13
140 15
187 11 T187S, T187I,