SCN5A Variant M390I Detail

We estimate the penetrance of LQTS for SCN5A M390I around 8% and the Brugada syndrome penetrance around 20%. SCN5A M390I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M390I is not present in gnomAD. M390I 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 M390I around 8% (0/10) and the Brugada syndrome penetrance around 20% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.854 23 7
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.

M390I has 60 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
333 15 c.998+1G>A, c.998+5G>A,
271 13 L271V,
1702 7
387 7
396 11 V396L, V396A,
385 11 A385T,
391 5
330 13 S330F,
388 6 I388S,
1698 9 A1698T,
332 13 A332T,
1707 14
1704 11 L1704H,
1706 11 Q1706H,
384 14 S384T,
1669 15
329 14
1668 11 M1668T,
1692 12
386 8 G386E, G386R,
1672 14 S1672Y,
1693 15
378 8
1699 10
331 12
402 15 F402L,
1665 11
267 15
379 12
1703 11
399 13
272 13
397 11 I397V, I397F, I397T,
1709 14 T1709M, T1709R, p.T1709del,
1701 8 M1701I,
392 8
1697 12
389 7 Y389X, Y389H,
395 9
393 7
390 0
394 6
383 14
264 14
1708 13 T1708I,
382 8
1696 14
374 12 W374G,
1705 7
1700 11
1661 14 G1661R, G1661E,
381 10 c.1141-3C>A, c.1140+1G>A,
375 14
1691 12
368 13
380 15
268 15 G268S,
377 13
398 12
1664 13