SCN5A Variant A265V Detail

We estimate the penetrance of LQTS for SCN5A A265V around 6% and the Brugada syndrome penetrance around 9%. SCN5A A265V was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A265V is present in 1 alleles in gnomAD. A265V has been functionally characterized in 0 papers. This residue is located in a Non_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 (0 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 A265V around 6% (0/11) and the Brugada syndrome penetrance around 9% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.9 1 -4.62 0.966 2 12
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 15 0 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.

A265V has 68 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 8
271 10 L271V,
266 4 L266H,
276 14 L276Q, L276P,
363 10
1544 14 T1544P,
270 9 Q270K,
360 11
1627 10
396 10 V396A, V396L,
1624 12 V1624I,
355 7 F355I, F355C,
1549 13
401 15 S401P,
356 11 D356N,
1543 12 V1543L, V1543A,
1542 10
361 5
260 9
366 11
365 6
258 10 V258A,
354 11
1546 8 M1546T,
369 11 M369K,
1545 10
1630 13 I1630R, I1630V,
1626 14 R1626L, R1626P, R1626C, R1626H,
267 6
1550 15
262 5 S262G,
357 9
256 14
399 14
272 10
397 14 I397F, I397V, I397T,
274 14 G274C,
362 6
261 7
273 11
1628 13
1539 15 C1539F, C1539Y,
392 9
389 14 Y389H, Y389X,
269 6
1620 15 T1620K, T1620M,
395 12
393 12
275 14 N275K,
264 6
259 10
1548 12 G1548K, E1548K,
265 0 A265V,
358 6
367 12 R367H, R367L, R367C,
263 6 V263I,
359 9 A359T, p.A359PfsX12,
1547 12 V1547L,
370 15 T370M,
1541 14
381 14 c.1141-3C>A, c.1140+1G>A,
368 10
268 5 G268S,
377 13
257 12
400 13 G400E, G400R, G400A,
353 13 T353I,
1623 12 R1623L, R1623Q, c.4867delC, R1623X,