SCN5A Variant M1668T Detail

We estimate the penetrance of LQTS for SCN5A M1668T around 6% and the Brugada syndrome penetrance around 11%. SCN5A M1668T was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M1668T is present in 1 alleles in gnomAD. M1668T has been functionally characterized in 0 papers. This residue is located in a Non_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 (1 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 M1668T around 6% (0/11) and the Brugada syndrome penetrance around 11% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.52 1 -1.5 0.95 6 5
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: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 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.

M1668T has 73 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
1702 9
1659 15
387 14
1304 15 T1304M,
1757 14
391 14
1698 10 A1698T,
1756 13 I1756V,
1314 14 c.3940_3941delCT,
1220 14 G1220E,
1673 10
1675 11
1764 12 V1764F, c.5290delG,
1666 7
1711 13 c.5131delG,
1754 13
1707 9
1694 12
1704 5 L1704H,
1706 11 Q1706H,
1716 14 p.L1716SfsX71,
1669 7
1671 7
1762 14 p.I1762del, I1762M,
1668 0 M1668T,
1676 12 M1676I, M1676T,
1692 14
1219 14 S1219N,
1672 7 S1672Y,
1767 15 Y1767C,
1660 12 I1660S, I1660V,
1693 14
1699 12
378 13
1310 14
402 14 F402L,
1665 5
1703 9
1663 9
397 14 I397F, I397V, I397T,
1759 9 S1759C,
1662 10
1709 11 T1709M, p.T1709del, T1709R,
1701 5 M1701I,
1307 12
1758 11 p.I1758del, I1758V,
1223 12 c.3667delG,
1755 8
1697 11
1222 15 L1222R, p.L1222LfsX7,
393 15
1674 12 F1674V,
1713 14
394 11
390 11
1708 7 T1708I,
1696 13
374 15 W374G,
1705 6
1700 8
1763 11 V1763L, V1763M,
1751 11
1311 13 L1311P,
1308 14 L1308F,
1760 14
1752 12
1670 7
1661 9 G1661E, G1661R,
1710 14 S1710L,
1679 14
398 12
1667 5 V1667I,
1664 6