SCN5A Variant M1652T Detail

We estimate the penetrance of LQTS for SCN5A M1652T around 75% and the Brugada syndrome penetrance around 10%. SCN5A M1652T was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. M1652T is not present in gnomAD. M1652T has been functionally characterized in 1 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 (3 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A M1652T around 75% (4/11) and the Brugada syndrome penetrance around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.58 0.999 -1.03 0.964 5 93
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
19716085 2009 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 11 3 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)
19716085 2009

M1652T has 62 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 12
1659 14
1643 14 I1643L,
1778 8
1480 14 c.4438-1C>T, c.4437+5G>A,
1773 10
1653 5
1771 9 I1771T,
1652 0 M1652R, M1652T,
1634 14 L1634P,
1777 8 V1777L, V1777M,
1650 7 L1650F,
1492 14
1656 9
1477 11 K1477N,
1779 12 T1779M,
1493 15 p.K1493del, K1493R, K1493X,
1776 10
1787 11 S1787N,
1767 13 Y1767C,
1660 15 I1660V, I1660S,
1654 8
1786 15 c.5356_5357delCT, L1786R, L1786Q,
1648 5
1769 13
1319 13 G1319V,
1649 4 A1649V,
1768 15 I1768V,
1774 5 c.5321_5324dupACTT, N1774D,
1473 14 F1473C, F1473S,
1644 12 R1644C, R1644L, R1644H,
1657 10
1496 12
1474 15
1481 14 G1481V, G1481E, G1481R,
1781 10 E1781D, E1781G,
1789 13
1318 14
1772 12 L1772V,
1499 15
1645 10 T1645M,
410 14 A410V,
1780 14 E1780G,
1788 9 c.5361_5364delTGAG,
1770 9 I1770V,
1651 6
1500 12 p.K1500del,
1791 14
1322 14 c.3963+2T>C, c.3963+4A>G,
1792 14 D1792V, D1792N, D1792Y,
407 13
1775 9 F1775V, p.F1775LfsX15,
1642 15 G1642E,
1655 8
1497 15
1790 15 D1790G, p.D1790del, D1790N,
406 14 N406K, N406S,
1647 10
1503 15 S1503Y,
1646 10
1782 14
1658 12