SCN5A Variant c.5131delG Detail

We estimate the penetrance of LQTS for SCN5A c.5131delG around 3% and the Brugada syndrome penetrance around 56%. SCN5A c.5131delG was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. c.5131delG is not present in gnomAD. c.5131delG has been functionally characterized in 1 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 (5 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 c.5131delG around 3% (0/11) and the Brugada syndrome penetrance around 56% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 78 1
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
19251209 2009 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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)
19251209 2009

c.5131delG 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 12
901 15 S901L, E901K,
896 14 C896S,
1417 9
1715 9
1687 11
1413 14
372 10
401 14 S401P,
1756 11 I1756V,
1764 13 V1764F, c.5290delG,
371 8 Q371E,
1711 0 c.5131delG,
1707 6
1694 15
1704 10 L1704H,
1706 5 Q1706H,
1716 8 p.L1716SfsX71,
1714 9 D1714G,
376 11 R376H, R376C,
1688 14
897 12 G897E, G897R,
1423 15 D1423H,
1668 13 M1668T,
1692 12
1753 14 T1753A,
1422 14 M1422R,
378 10
1418 11
402 14 F402L,
373 8
1712 4 G1712S, G1712C,
379 10
1703 9
898 11
893 15 R893C, R893H,
397 12 I397F, I397T, I397V,
1759 11 S1759C,
1719 14
1709 5 T1709M, p.T1709del, T1709R,
1701 14 M1701I,
1420 11 G1420P, G1420D, G1420R, G1420V,
900 14
1755 11
393 13
1713 5
394 15
1708 8 T1708I,
382 15
1421 12
1718 14 S1718R,
374 6 W374G,
1705 10
1700 14
1717 11 L1717P,
367 12 R367H, R367C, R367L,
1751 14
1416 13 A1416E, c.4245+1G>A, c.4245+1G>C, c.4245+2T>A, A1416G,
1760 10
370 12 T370M,
1752 11
1761 14 c.5280delG, L1761H, L1761F,
1686 13
375 5
368 12
899 15
1710 4 S1710L,
380 14
1415 14
377 11
1419 6 K1419E,
1414 11 Q1414H,
1664 15