SCN5A Variant M414T Detail

We estimate the penetrance of LQTS for SCN5A M414T around 19% and the Brugada syndrome penetrance around 13%. SCN5A M414T was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M414T is not present in gnomAD. M414T 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 (1 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 M414T around 19% (0/10) and the Brugada syndrome penetrance around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.931 9 23
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 14 0 1 - -
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.

M414T has 66 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
414 0 M414V,
939 12 L939F,
1643 14 I1643L,
937 14
1778 10
1773 12
249 7 K249X,
247 12 V247L,
1771 13 I1771T,
1777 11 V1777L, V1777M,
418 6 E418K,
250 10
409 9 L409V, L409P,
928 15 L928P,
1650 15 L1650F,
417 7
933 11
246 8
935 13 L935P,
1779 7 T1779M,
412 6 V412D,
1470 14
245 9 Q245K,
1776 7
244 13
1769 14
415 4 A415T,
1649 13 A1649V,
1768 15 I1768V,
940 13 S940N,
1774 13 c.5321_5324dupACTT, N1774D,
405 15
420 11
248 12
241 12
419 10 Q419X,
1781 13 E1781G, E1781D,
930 15 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1772 10 L1772V,
1645 12 T1645M,
239 14 I239V , I239V,
251 14
410 6 A410V,
1780 9 E1780G,
242 10 A242D,
929 13
416 9 Y416C,
413 5 A413E, A413T,
408 10
253 12
407 10
1783 11
936 10
238 14
422 13
1775 7 p.F1775LfsX15, F1775V,
1642 12 G1642E,
421 11
406 13 N406K, N406S,
252 13
411 5 V411M,
243 13
932 12
1646 11
1489 15 E1489D,
1782 11