SCN5A Variant A361G Detail

We estimate the penetrance of LQTS for SCN5A A361G around 8% and the Brugada syndrome penetrance around 25%. SCN5A A361G was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A361G is not present in gnomAD. A361G has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 A361G around 8% (0/10) and the Brugada syndrome penetrance around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.963 30 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: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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.

A361G has 69 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 5
277 13
271 11 L271V,
266 8 L266H,
276 11 L276Q, L276P,
363 6
348 14 P348A,
270 11 Q270K,
360 6
1627 15
396 12 V396A, V396L,
355 5 F355C, F355I,
1549 12
372 14
356 7 D356N,
1543 15 V1543L, V1543A,
1542 14
361 0
904 13 W904X,
260 13
366 10
365 6
258 13 V258A,
354 7
1546 10 M1546T,
369 12 M369K,
1545 13
349 15 D349N,
267 10
1550 13
262 9 S262G,
357 6
272 9
274 12 G274C,
362 5
261 9
273 10
920 14
900 13
392 12
269 7
393 13
916 13
275 13 N275K,
264 10
912 14 Q912R,
259 14
347 12
1548 12 E1548K, G1548K,
351 12 G351C, G351D, G351V, G351S,
265 5 A265V,
374 15 W374G,
358 5
903 14 p.M903CfsX29,
367 10 R367H, R367C, R367L,
263 11 V263I,
359 5 A359T, p.A359PfsX12,
1547 13 V1547L,
370 14 T370M,
381 13 c.1140+1G>A, c.1141-3C>A,
352 11 Y352C,
368 10
899 14
380 14
268 7 G268S,
377 11
257 14
353 9 T353I,
907 14