SCN5A Variant R367G Detail

We estimate the penetrance of LQTS for SCN5A R367G around 13% and the Brugada syndrome penetrance around 49%. SCN5A R367G was found in a total of 0 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R367G is not present in gnomAD. R367G has been functionally characterized in 1 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 (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 R367G around 13% (0/10) and the Brugada syndrome penetrance around 49% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.87 0.999 -4.2 0.972 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
28534967 2017 1 0 0 1 CCD
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
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)
28534967 2017

R367G 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 S901L, E901K,
276 13 L276P, L276Q,
363 6
896 15 C896S,
404 15 L404Q, L404V,
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 G897E, G897R,
927 15 N927K, N927S,
369 9 M369K,
378 12
902 12
402 15 F402L,
349 11 D349N,
373 6
1712 14 G1712C, G1712S,
379 13
898 10
893 13 R893C, R893H,
922 15 V922I,
272 14
397 11 I397V, I397T, I397F,
405 14
362 10
261 12
920 11
1709 13 p.T1709del, T1709M, T1709R,
900 6
392 13
393 11
916 12
264 13
347 14
351 13 G351D, G351S, G351V, G351C,
265 12 A265V,
374 8 W374G,
350 12 H350Q,
358 15
903 9 p.M903CfsX29,
367 0 R367H, R367L, R367C,
359 13 A359T, p.A359PfsX12,
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 G400R, G400E, G400A,
1419 14 K1419E,
353 9 T353I,
907 13