SCN5A Variant E1548K Detail

We estimate the penetrance of LQTS for SCN5A E1548K around 3% and the Brugada syndrome penetrance around 51%. SCN5A E1548K was found in a total of 4 carriers in 4 papers and/or in gnomAD: 3 had Brugada syndrome, 0 had LQTS. E1548K is present in 1 alleles in gnomAD. E1548K has been functionally characterized in 4 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 E1548K around 3% (0/14) and the Brugada syndrome penetrance around 51% (7/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.63 0.902 2.97 0.958 64 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
17404158 2007 1 0 1 0
26921764 2016 1 0 1 0
20129283 2010 3 0 3 0
29325976 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 4 1 0 3 -
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)
29325976 2018
17404158 2007
26921764 2016
20129283 2010

E1548K has 55 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
277 15
271 12 L271V,
266 9 L266H,
1544 7 T1544P,
270 7 Q270K,
360 15
1627 13
1567 14 F1567L,
1624 14 V1624I,
1552 8 Q1552R, Q1552L,
355 12 F355C, F355I,
1549 5
1556 8
356 9 D356N,
1543 10 V1543L, V1543A,
1558 12
1542 11
1557 8 I1557V,
361 12
1562 14
1564 11
354 14
1546 7 M1546T,
1545 6
1626 12 R1626L, R1626P, R1626H, R1626C,
267 12
1550 9
1560 7 L1560F,
262 14 S262G,
357 9
272 13
274 12 G274C,
273 7
1559 11 I1559V,
1553 10 S1553R,
269 7
1620 14 T1620K, T1620M,
275 14 N275K,
1548 0 G1548K, E1548K,
1555 13 E1555K,
265 12 A265V,
1619 13 P1619L, P1619Q, c.4856delC,
358 10
1551 9 D1551N, D1551Y,
263 15 V263I,
359 13 A359T, p.A359PfsX12,
1547 5 V1547L,
1563 11
1541 11
1554 12
1540 14
268 11 G268S,
1622 14
1561 11
1623 10 R1623X, c.4867delC, R1623Q, R1623L,