SCN5A Variant V396A Detail

We estimate the penetrance of LQTS for SCN5A V396A around 11% and the Brugada syndrome penetrance around 53%. SCN5A V396A was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. V396A is not present in gnomAD. V396A 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 V396A around 11% (0/11) and the Brugada syndrome penetrance around 53% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.92 0.999 -2.38 0.977 71 19
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)
20129283 2010

V396A has 66 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
403 10
364 10
271 13 L271V,
266 13 L266H,
363 13
404 10 L404Q, L404V,
1627 14
396 0 V396L, V396A,
1624 14 V1624I,
355 12 F355C, F355I,
391 10
372 13
401 7 S401P,
388 15 I388S,
371 9 Q371E,
361 12
260 9
366 10
365 7
1706 14 Q1706H,
258 14 V258A,
369 7 M369K,
1767 14 Y1767C,
378 11
402 9 F402L,
373 14
267 9
262 12 S262G,
256 14
399 7
272 12
397 4 I397T, I397V, I397F,
405 12
1657 15
362 12
261 9
1709 12 p.T1709del, T1709R, T1709M,
1628 15
392 6
389 12 Y389X, Y389H,
269 14
395 5
393 6
390 11
394 7
1658 15
264 6
1708 14 T1708I,
259 13
382 14
265 10 A265V,
374 10 W374G,
1705 12
358 15
367 11 R367C, R367L, R367H,
263 10 V263I,
370 10 T370M,
1661 15 G1661E, G1661R,
381 13 c.1140+1G>A, c.1141-3C>A,
406 14 N406S, N406K,
368 5
268 10 G268S,
377 11
398 8
257 12
400 6 G400E, G400A, G400R,