SCN5A Variant N1463Y Detail

We estimate the penetrance of LQTS for SCN5A N1463Y around 7% and the Brugada syndrome penetrance around 53%. SCN5A N1463Y was found in a total of 1 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. N1463Y is not present in gnomAD. N1463Y has been functionally characterized in 2 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 (4 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 N1463Y around 7% (0/11) and the Brugada syndrome penetrance around 53% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.64 0.889 -4.06 0.951 70 6
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
20129283 2010 1 0 1 0
29325976 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 0 4 - -
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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
20129283 2010
29325976 2018

N1463Y has 81 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
939 10 L939F,
896 12 C896S,
937 10
895 13 L895F,
1417 11
1765 9
839 13 L839P,
842 13
1340 13 V1340I,
1457 8
1453 13
1757 14
1455 11
1756 14 I1756V,
1461 6 T1461S,
926 14
1764 12 V1764F, c.5290delG,
409 11 L409P, L409V,
1333 15
1344 14 F1344L, F1344S,
928 14 L928P,
934 7
1458 7 S1458Y,
933 11
1471 13
935 6 L935P,
412 14 V412D,
897 14 G897E, G897R,
1762 12 I1762M, p.I1762del,
1470 11
1464 5 L1464P, c.4389_4396delCCTCTTTA,
927 12 N927S, N927K,
1466 6 c.4396_4397insG,
1769 13
1418 12
1766 14 M1766L, M1766V, M1766T,
1768 11 I1768V,
940 14 S940N,
1334 13 I1334V,
1341 11
1468 10 V1468F, V1468A,
405 13
831 15
1462 4
938 7
1759 15 S1759C,
942 11
843 14 T843A,
1456 11
930 12 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1459 7 c.4376_4379delTCTT,
1772 14 L1772V,
1460 7 F1460L,
1454 11
1338 13 L1338V,
410 15 A410V,
929 14
416 15 Y416C,
413 14 A413T, A413E,
1345 13 W1345C,
941 13 S941N, S941F,
1337 11
846 15 L846R,
936 10
1763 15 V1763M, V1763L,
1416 10 c.4245+1G>C, A1416E, c.4245+1G>A, A1416G, c.4245+2T>A,
1465 7 p.F1465_L1480dup,
1760 10
1467 8
1761 9 c.5280delG, L1761F, L1761H,
1469 11 I1469V,
406 13 N406S, N406K,
1710 14 S1710L,
1415 14
932 9
832 14
835 15 S835L, S835A,
828 14 L828V,
931 8
1463 0 N1463Y,
1413 14