SCN5A Variant H350N Detail

We estimate the penetrance of LQTS for SCN5A H350N around 4% and the Brugada syndrome penetrance around 30%. SCN5A H350N was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. H350N is not present in gnomAD. H350N has been functionally characterized in 0 papers. This residue is located in a 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 (3 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 H350N around 4% (0/10) and the Brugada syndrome penetrance around 30% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.744 41 2
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 12 0 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.

H350N has 54 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 13
277 14
901 8 E901K, S901L,
919 15
870 13
276 13 L276Q, L276P,
363 12
348 7 P348A,
360 11
279 15
372 14
356 15 D356N,
904 5 W904X,
376 11 R376H, R376C,
871 9
354 11
909 10
868 14 c.2602delC, L868X,
902 10
349 5 D349N,
373 13
911 12 G911E,
325 15 L325R,
900 9
324 15
321 14 S321Y,
872 9 D872N,
345 13
865 14
916 14
912 11 Q912R,
323 13
347 8
906 10
351 5 G351D, G351S, G351C, G351V,
874 14 G874D,
910 13 S910L,
878 15 R878C, R878L, R878H,
350 0 H350Q,
903 9 p.M903CfsX29,
367 12 R367L, R367H, R367C,
346 10 E346D, E346X, E346G, E346K,
877 13
322 11
905 7
352 6 Y352C,
915 13 C915R,
899 13
380 13
377 13
908 6
873 13 S873A,
353 8 T353I,
907 8