SCN5A Variant G1661R Detail

We estimate the penetrance of LQTS for SCN5A G1661R around 3% and the Brugada syndrome penetrance around 66%. SCN5A G1661R was found in a total of 7 carriers in 5 papers and/or in gnomAD: 7 had Brugada syndrome, 0 had LQTS. G1661R is not present in gnomAD. G1661R has been functionally characterized in 6 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 G1661R around 3% (0/17) and the Brugada syndrome penetrance around 66% (11/17).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.49 0.998 -3.52 0.974 52 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
26921764 2016 1 0 1 0
28781330 2017 7 0 7 0
20129283 2010 2 0 2 0
20129283 2010 1 0 1 0
29325976 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 7 0 0 7 -
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
26921764 2016
28781330 2017
20129283 2010
20129283 2010
32533946 2020 HEK 5

G1661R has 64 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 6
1765 13
396 15 V396L, V396A,
1653 12
391 14
1315 13
1771 14 I1771T,
401 14 S401P,
1314 10 c.3940_3941delCT,
1320 9 M1320I,
1764 10 c.5290delG, V1764F,
1666 9
1656 9
1704 13 L1704H,
1669 12
1671 15
1762 13 I1762M, p.I1762del,
1668 9 M1668T,
1767 8 Y1767C,
1313 14
1660 4 I1660V, I1660S,
1654 11
1310 14
1769 14
402 10 F402L,
1766 10 M1766L, M1766V, M1766T,
1319 11 G1319V,
1665 7
1768 13 I1768V,
1473 15 F1473C, F1473S,
1663 5
399 11
397 12 I397T, I397F, I397V,
1657 7
1759 11 S1759C,
1662 4
1324 13
1317 11 F1317C,
1327 13
1709 13 p.T1709del, T1709R, T1709M,
1701 13 M1701I,
1758 13 p.I1758del, I1758V,
1755 14
1318 14
395 13
1323 10 V1323G,
394 10
390 14
1770 12 I1770V,
1708 11 T1708I,
1705 11
1322 13 c.3963+2T>C, c.3963+4A>G,
1326 15 A1326S,
1763 9 V1763M, V1763L,
1311 13 L1311P,
1670 13
1661 0 G1661R, G1661E,
1655 10
398 7
400 14 G400R, G400A, G400E,
1667 9 V1667I,
1664 4
1658 7