SCN5A Variant Y352H Detail

We estimate the penetrance of LQTS for SCN5A Y352H around 5% and the Brugada syndrome penetrance around 52%. SCN5A Y352H was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Y352H is not present in gnomAD. Y352H 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 (5 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 Y352H around 5% (0/10) and the Brugada syndrome penetrance around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.969 79 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 10 0 5 - -
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.

Y352H 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 10
277 12
901 12 S901L, E901K,
919 14
276 12 L276P, L276Q,
363 9
348 9 P348A,
360 5
355 12 F355C, F355I,
356 10 D356N,
361 11
904 6 W904X,
366 15
365 15
376 14 R376C, R376H,
871 14
354 8
909 12
902 13
349 9 D349N,
1550 15
357 10
274 14 G274C,
362 13
911 10 G911E,
900 10
872 15 D872N,
345 12
917 15 L917R, L917V,
913 12
916 11
912 7 Q912R,
347 7
906 11
351 4 G351S, G351C, G351V, G351D,
910 12 S910L,
350 6 H350Q,
358 14
903 9 p.M903CfsX29,
367 12 R367L, R367H, R367C,
346 9 E346X, E346D, E346G, E346K,
359 10 p.A359PfsX12, A359T,
344 15 A344S,
322 14
905 10
352 0 Y352C,
915 12 C915R,
899 13
380 14
377 13
908 8
914 15
353 6 T353I,
907 7