SCN5A Variant G268S Detail

We estimate the penetrance of LQTS for SCN5A G268S around 7% and the Brugada syndrome penetrance around 11%. SCN5A G268S was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. G268S is present in 1 alleles in gnomAD. G268S has been functionally characterized in 0 papers. This residue is located in a Non_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 (1 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 G268S around 7% (0/11) and the Brugada syndrome penetrance around 11% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.62 1 -0.74 0.974 6 6
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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 1 - -
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.

G268S 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 9
277 13
271 5 L271V,
266 6 L266H,
276 10 L276Q, L276P,
363 12
1544 15 T1544P,
270 6 Q270K,
360 12
1627 10
396 10 V396A, V396L,
385 12 A385T,
1624 10 V1624I,
355 5 F355I, F355C,
1549 12
391 13
278 14 H278R, H278D,
388 14 I388S,
356 9 D356N,
1543 15 V1543L, V1543A,
1542 12
361 7
260 13
366 14
365 8
384 13 S384T,
354 9
386 13 G386E, G386R,
1546 10 M1546T,
369 14 M369K,
378 14
1545 10
1626 14 R1626L, R1626P, R1626C, R1626H,
267 4
1550 12
1625 14
262 10 S262G,
357 10
272 5
397 14 I397F, I397V, I397T,
274 10 G274C,
362 11
261 11
273 8
1628 14
392 7
389 10 Y389H, Y389X,
269 4
1620 11 T1620K, T1620M,
395 11
393 10
394 15
390 15
275 9 N275K,
264 8
259 15
347 15
382 14
1548 11 G1548K, E1548K,
265 5 A265V,
1619 13 P1619L, c.4856delC, P1619Q,
358 9
367 13 R367H, R367L, R367C,
263 9 V263I,
359 11 A359T, p.A359PfsX12,
1547 13 V1547L,
381 10 c.1141-3C>A, c.1140+1G>A,
368 11
380 14
268 0 G268S,
377 12
1622 15
1621 13
353 12 T353I,
1623 10 R1623L, R1623Q, c.4867delC, R1623X,