SCN5A Variant R367C Detail

We estimate the penetrance of LQTS for SCN5A R367C around 21% and the Brugada syndrome penetrance around 45%. SCN5A R367C was found in a total of 8 carriers in 8 papers and/or in gnomAD: 3 had Brugada syndrome, 2 had LQTS. R367C is present in 3 alleles in gnomAD. R367C has been functionally characterized in 9 papers. This residue is located in a Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (5 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 R367C around 21% (2/18) and the Brugada syndrome penetrance around 45% (8/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.85 1 -4.45 0.956 71 15
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
12106943 2002 1 0 1 0
21273195 2011 3 0 3 0
22885917 2012 1 0 1 0
26921764 2016 1 0 1 0
19251209 2009 1 0 1 0
19716085 2009 2 2 0 0
20129283 2010 2 0 2 0
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 8 3 2 3 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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)
12106943 2002
21273195 2011
22885917 2012
26921764 2016
19251209 2009
19716085 2009
20129283 2010
30059973 2018
32533946 2020 HEK 1

R367C has 75 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
364 5
919 13
901 11 E901K, S901L,
276 13 L276Q, L276P,
363 6
896 15 C896S,
404 15 L404V, L404Q,
348 13 P348A,
360 11
396 11 V396A, V396L,
894 12 I894M,
355 11 F355I, F355C,
372 4
401 12 S401P,
371 8 Q371E,
1711 12 c.5131delG,
928 15 L928P,
361 10
904 9 W904X,
366 7
365 7
1706 13 Q1706H,
376 9 R376H, R376C,
354 11
897 10 G897R, G897E,
927 15 N927S, N927K,
369 9 M369K,
378 12
902 12
402 15 F402L,
349 11 D349N,
373 6
1712 14 G1712S, G1712C,
379 13
898 10
893 13 R893C, R893H,
922 15 V922I,
272 14
397 11 I397F, I397T, I397V,
405 14
362 10
261 12
920 11
1709 13 T1709R, T1709M, p.T1709del,
900 6
392 13
393 11
916 12
264 13
347 14
351 13 G351S, G351C, G351V, G351D,
265 12 A265V,
374 8 W374G,
350 12 H350Q,
358 15
903 9 p.M903CfsX29,
367 0 R367C, R367L, R367H,
359 13 p.A359PfsX12, A359T,
370 7 T370M,
381 12 c.1141-3C>A, c.1140+1G>A,
923 11
905 14
375 10
352 12 Y352C,
368 5
899 6
1710 14 S1710L,
380 12
915 15 C915R,
268 13 G268S,
377 6
400 13 G400E, G400R, G400A,
1419 14 K1419E,
353 9 T353I,
907 13