SCN5A Variant Y403C Detail

We estimate the penetrance of LQTS for SCN5A Y403C around 32% and the Brugada syndrome penetrance around 13%. SCN5A Y403C was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Y403C is not present in gnomAD. Y403C has been functionally characterized in 0 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a 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 Y403C around 32% (1/10) 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 0.984 9 41
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.

Y403C has 68 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 0
1659 13
1643 14 I1643L,
404 6 L404V, L404Q,
1773 14
1765 13
396 10 V396L, V396A,
1653 8
254 14
1771 7 I1771T,
401 7 S401P,
1652 12 M1652T, M1652R,
1634 14 L1634P,
1764 11 V1764F, c.5290delG,
371 13 Q371E,
409 12 L409P, L409V,
928 15 L928P,
1650 6 L1650F,
260 10
366 15
1656 11
365 15
369 10 M369K,
1767 7 Y1767C,
1660 11 I1660S, I1660V,
1654 8
1648 13
1769 11
402 6 F402L,
1766 14 M1766V, M1766T, M1766L,
1649 10 A1649V,
1768 9 I1768V,
1774 12 c.5321_5324dupACTT, N1774D,
256 11
399 6
397 9 I397V, I397T, I397F,
405 8
1657 7
261 13
1709 15 T1709M, p.T1709del, T1709R,
1772 11 L1772V,
1645 15 T1645M,
395 11
394 12
410 12 A410V,
1770 10 I1770V,
1658 10
264 13
1651 11
259 14
408 11
253 12
407 8
1763 14 V1763M, V1763L,
263 14 V263I,
1775 12 F1775V, p.F1775LfsX15,
370 13 T370M,
1661 12 G1661R, G1661E,
1655 11
406 7 N406K, N406S,
368 13
411 14 V411M,
398 7
1647 10
257 11
400 5 G400E, G400A, G400R,
1646 11
1664 14