SCN5A Variant V1777M Detail

We estimate the penetrance of LQTS for SCN5A V1777M around 29% and the Brugada syndrome penetrance around 5%. SCN5A V1777M was found in a total of 12 carriers in 6 papers and/or in gnomAD: 0 had Brugada syndrome, 3 had LQTS. V1777M is present in 5 alleles in gnomAD. V1777M has been functionally characterized in 7 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 V1777M around 29% (4/22) and the Brugada syndrome penetrance around 5% (1/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.7 1 -2.47 0.927 7 55
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
15840476 2005 1 1 0 0
25904541 2015 1 1 0 0
27566755 2016 2 2 0 0
11463728 2001 6 1 0 1 2:1 AV block
19716085 2009 1 1 0 0
30059973 2018 8 8 0 0
LITERATURE, COHORT, AND GNOMAD: - 12 9 3 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.

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)
12085742 2002
15840476 2005
25904541 2015
27566755 2016
11463728 2001 HEK-tSA202 -8.99 -12.43 1320
19716085 2009
30059973 2018

V1777M has 67 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
414 11 M414V,
1785 10
1778 4
1480 14 c.4438-1C>T, c.4437+5G>A,
1773 7
1653 11
1771 11 I1771T,
1652 8 M1652R, M1652T,
1777 0 V1777L, V1777M,
1487 14 M1487K, M1487L,
418 15 E418K,
409 15 L409V, L409P,
1650 12 L1650F,
1492 9
1656 15
417 14
1477 9 K1477N,
1491 14 Q1491H,
1471 14
1779 6 T1779M,
1493 8 p.K1493del, K1493R, K1493X,
1470 13
1478 11 K1478E,
1776 4
1787 11 S1787N,
1786 12 c.5356_5357delCT, L1786R, L1786Q,
1648 10
1769 12
415 15 A415T,
1495 13 Y1495S,
1649 8 A1649V,
1774 6 c.5321_5324dupACTT, N1774D,
1473 13 F1473C, F1473S,
1496 9
1474 10
1481 12 G1481V, G1481E, G1481R,
1781 5 E1781D, E1781G,
1789 15
1772 10 L1772V,
1499 14
1645 11 T1645M,
1488 13 T1488R,
1784 12 E1784K, E1784X,
410 11 A410V,
1780 6 E1780G,
1788 12 c.5361_5364delTGAG,
1770 11 I1770V,
1651 13
1500 12 p.K1500del,
413 13 A413E, A413T,
1791 15
1482 13
407 14
1783 10
1476 15 Q1476R, Q1476X,
1775 7 F1775V, p.F1775LfsX15,
1642 14 G1642E,
1497 12
1490 12
1475 14 Q1475L, p.Q1475NfsX6,
1790 15 D1790G, p.D1790del, D1790N,
1494 15
411 13 V411M,
1647 14
1646 11
1489 9 E1489D,
1782 9