SCN5A Variant F402Y Detail

We estimate the penetrance of LQTS for SCN5A F402Y around 21% and the Brugada syndrome penetrance around 12%. SCN5A F402Y was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F402Y is not present in gnomAD. F402Y 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 (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A F402Y around 21% (1/10) and the Brugada syndrome penetrance around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.965 7 25
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 1 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.

F402Y has 74 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 6
1659 14
404 8 L404Q, L404V,
1765 10
396 9 V396L, V396A,
1653 12
391 15
372 14
1771 9 I1771T,
401 4 S401P,
1764 7 c.5290delG, V1764F,
371 8 Q371E,
409 12 L409P, L409V,
1711 14 c.5131delG,
928 14 L928P,
1650 12 L1650F,
260 14
366 14
1707 14
1656 13
365 14
1706 14 Q1706H,
1762 14 p.I1762del, I1762M,
1668 14 M1668T,
1466 13 c.4396_4397insG,
369 9 M369K,
1767 5 Y1767C,
1660 10 I1660S, I1660V,
1654 12
1769 11
402 0 F402L,
1766 11 M1766L, M1766T, M1766V,
1665 15
1768 8 I1768V,
1663 13
399 7
397 6 I397T, I397V, I397F,
405 7
1657 9
1759 11 S1759C,
261 14
1662 14
1709 9 p.T1709del, T1709M, T1709R,
392 14
1772 13 L1772V,
395 11
393 12
390 15
394 10
410 14 A410V,
1770 11 I1770V,
264 14
1658 12
1708 10 T1708I,
408 12
374 12 W374G,
1705 12
407 11
367 15 R367L, R367H, R367C,
1763 10 V1763M, V1763L,
1760 11
370 10 T370M,
1661 10 G1661R, G1661E,
1761 14 L1761F, L1761H, c.5280delG,
1655 14
1469 15 I1469V,
406 7 N406S, N406K,
368 11
1710 12 S1710L,
932 14
398 5
257 14
400 6 G400R, G400A, G400E,
1664 10