SCN5A Variant G351C Detail

We estimate the penetrance of LQTS for SCN5A G351C around 5% and the Brugada syndrome penetrance around 54%. SCN5A G351C was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. G351C is not present in gnomAD. G351C has been functionally characterized in 1 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 G351C around 5% (0/11) and the Brugada syndrome penetrance around 54% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.79 1 -3.79 0.973 70 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
29325976 2018 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)
29325976 2018

G351C has 57 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 12
277 9
901 13 S901L, E901K,
276 10 L276P, L276Q,
363 11
348 6 P348A,
360 8
279 12
355 11 F355I, F355C,
1549 15
278 14 H278D, H278R,
356 10 D356N,
361 12
904 8 W904X,
343 14
376 12 R376C, R376H,
871 13
354 7
909 14
902 15
349 7 D349N,
1550 13
357 11
911 13 G911E,
272 15
274 12 G274C,
273 15
325 13 L325R,
900 12
324 14
321 13 S321Y,
872 13 D872N,
345 9
916 14
275 14 N275K,
912 10 Q912R,
323 13
347 4
906 14
351 0 G351V, G351C, G351S, G351D,
910 15 S910L,
350 5 H350Q,
903 12 p.M903CfsX29,
367 13 R367L, R367C, R367H,
346 6 E346G, E346X, E346K, E346D,
359 12 p.A359PfsX12, A359T,
344 12 A344S,
381 15 c.1141-3C>A, c.1140+1G>A,
322 11
905 12
352 4 Y352C,
915 15 C915R,
380 12
377 12
908 10
353 5 T353I,
907 10