SCN5A Variant V258A Detail

We estimate the penetrance of LQTS for SCN5A V258A around 71% and the Brugada syndrome penetrance around 8%. SCN5A V258A was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. V258A is not present in gnomAD. V258A has been functionally characterized in 1 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (0 diagnosed with Brugada syndrome) and 5 individuals for LQTS (3 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A V258A around 71% (4/11) and the Brugada syndrome penetrance around 8% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.83 0.999 -0.85 0.937 0 91
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
27871843 2017 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 12 3 0 - -
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)
27871843 2017

V258A has 52 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 14
266 12 L266H,
363 13
1643 12 I1643L,
404 11 L404Q, L404V,
396 14 V396L, V396A,
254 7
401 14 S401P,
1634 14 L1634P,
1543 14 V1543L, V1543A,
250 12
1542 12
928 15 L928P,
361 13
260 6
366 10
365 11
258 0 V258A,
924 14 V924I,
1546 12 M1546T,
369 11 M369K,
1630 13 I1630V, I1630R,
267 14
262 6 S262G,
256 7
405 14
362 8
261 5
920 13
1539 13 C1539Y, C1539F,
255 6
917 15 L917V, L917R,
251 11
264 11
259 6
1633 13
265 10 A265V,
1637 15
408 14
253 9
407 13
358 11
263 9 V263I,
359 13 A359T, p.A359PfsX12,
370 14 T370M,
1631 14 G1631D,
368 14
252 11
1647 14
257 4
400 12 G400A, G400R, G400E,
1646 15