SCN5A Variant I397M Detail

We estimate the penetrance of LQTS for SCN5A I397M around 40% and the Brugada syndrome penetrance around 23%. SCN5A I397M was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I397M is not present in gnomAD. I397M has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 diagnosed with Brugada syndrome) and 5 individuals for LQTS (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A I397M around 40% (2/10) and the Brugada syndrome penetrance around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.848 28 53
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 11 2 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.

I397M has 72 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 9
364 12
1702 14
363 15
404 10 L404V, L404Q,
1765 15
396 4 V396L, V396A,
355 15 F355I, F355C,
391 11
372 11
1771 15 I1771T,
401 5 S401P,
1764 11 V1764F, c.5290delG,
371 6 Q371E,
1711 12 c.5131delG,
260 12
366 11
1707 13
365 9
1704 14 L1704H,
1706 11 Q1706H,
897 15 G897E, G897R,
1668 14 M1668T,
369 7 M369K,
1767 11 Y1767C,
1660 14 I1660S, I1660V,
378 10
402 6 F402L,
373 13
1768 14 I1768V,
267 14
379 15
399 7
397 0 I397F, I397V, I397T,
405 10
1657 13
362 15
1759 14 S1759C,
261 12
1709 8 T1709M, p.T1709del, T1709R,
1701 15 M1701I,
392 9
389 14 Y389H, Y389X,
395 7
393 7
390 11
394 7
264 10
1708 10 T1708I,
382 15
265 14 A265V,
374 7 W374G,
1705 9
407 15
367 11 R367H, R367L, R367C,
1763 14 V1763L, V1763M,
263 14 V263I,
1760 14
370 9 T370M,
1661 12 G1661R, G1661E,
381 14 c.1140+1G>A, c.1141-3C>A,
375 13
406 12 N406K, N406S,
368 6
1710 12 S1710L,
268 14 G268S,
377 11
398 6
257 14
400 6 G400E, G400A, G400R,
1664 12
1658 14