SCN5A Variant M394R Detail

We estimate the penetrance of LQTS for SCN5A M394R around 22% and the Brugada syndrome penetrance around 36%. SCN5A M394R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M394R is not present in gnomAD. M394R has been functionally characterized in 0 papers. This residue is located in a 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 (3 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A M394R around 22% (1/10) and the Brugada syndrome penetrance around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.952 50 26
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 1 3 - -
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.

M394R 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
403 12
271 14 L271V,
1702 11
1659 15
387 12
396 7 V396A, V396L,
391 5
388 11 I388S,
1698 14 A1698T,
401 11 S401P,
1764 14 c.5290delG, V1764F,
1666 15
371 12 Q371E,
1711 15 c.5131delG,
1707 14
365 13
1704 12 L1704H,
1706 12 Q1706H,
1668 11 M1668T,
386 13 G386R, G386E,
369 13 M369K,
1767 13 Y1767C,
1660 13 I1660S, I1660V,
378 10
1654 15
402 10 F402L,
1665 10
267 13
1703 14
1663 14
399 8
272 15
397 7 I397V, I397F, I397T,
1657 13
1759 15 S1759C,
1662 12
1709 11 p.T1709del, T1709R, T1709M,
1701 10 M1701I,
392 7
389 11 Y389H, Y389X,
395 5
393 6
390 6
394 0
264 11
1708 11 T1708I,
382 12
374 11 W374G,
1705 7
1700 14
1661 10 G1661R, G1661E,
381 13 c.1140+1G>A, c.1141-3C>A,
368 11
268 15 G268S,
377 14
398 6
400 10 G400E, G400R, G400A,
1667 15 V1667I,
1664 10
1658 12