SCN5A Variant R121W Detail

We estimate the penetrance of LQTS for SCN5A R121W around 2% and the Brugada syndrome penetrance around 60%. SCN5A R121W was found in a total of 3 carriers in 5 papers and/or in gnomAD: 3 had Brugada syndrome, 0 had LQTS. R121W is not present in gnomAD. R121W has been functionally characterized in 7 papers. This residue is located in a 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 R121W around 2% (0/13) and the Brugada syndrome penetrance around 60% (7/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.57 1 -7.16 0.889 65 1
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
20395683 2010 2 0 0 2 syncopes, SSS, atrial flutter, episodes of VT and PCCD
19606473 2009 1 0 1 0
26173111 2015 1 0 1 0
20129283 2010 1 0 1 0
29325976 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 3 0 0 3 -
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)
19606473 2009
26173111 2015
20129283 2010
20395683 2010 0
22739120 2012 HEK 0
29325976 2018
32533946 2020 HEK 1

R121W has 34 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
126 9 K126E,
175 11 K175N,
113 10 V113I, V113A,
129 12
188 14
178 5 A178G,
128 10 c.381dupT,
117 8
179 7 R179X, R179Q,
119 7 P119L, P119S,
177 6 L177P,
123 7 A123G, A123V,
121 0 R121Q, R121W,
127 11
124 6 A124D,
118 6
125 6 V125L,
181 11
176 9
172 14
174 9 V174I,
185 14 A185T, A185V,
115 6 S115G,
182 14 C182R, C182Y,
173 11
112 10 Y112C,
114 6
184 11 H184R,
170 14 F170I,
116 6
180 8 G180V,
120 6
183 14
122 5