SCN5A Variant R340Q Detail

We estimate the penetrance of LQTS for SCN5A R340Q around 10% and the Brugada syndrome penetrance around 4%. SCN5A R340Q was found in a total of 22 carriers in 5 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. R340Q is present in 21 alleles in gnomAD. R340Q has been functionally characterized in 5 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 R340Q around 10% (2/32) and the Brugada syndrome penetrance around 4% (1/32).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.21 0.984 0.59 0.581 5 43
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
22685113 2012 1 0 0 1 AF
15176425 2004 1 1 0 0
21306642 2011 1 0 0 1 AF
24144883 2014 1 0 0 1 AF
24631775 2014 1 0 0 1 SD
LITERATURE, COHORT, AND GNOMAD: - 22 21 1 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)
22685113 2012 HEK 86 -6.2 -5.5
15176425 2004
21306642 2011
24144883 2014
24631775 2014

R340Q has 31 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
343 12
328 11
341 6 C341Y,
342 6
326 11
335 9 C335S, C335R,
327 10
339 7
319 12 G319S, G319R, G319C,
384 14 S384T,
325 14 L325R,
317 14 K317N, K317E, K317M,
284 10
336 10 P336L,
282 9 R282H, R282C,
279 11
321 15 S321Y,
344 12 A344S,
340 0 R340W, R340Q,
338 7
285 14 T285K,
345 14
278 11 H278D, H278R,
334 12 c.999-424_1338+81del,
280 8 C280Y,
281 6 V281M,
318 15
323 14
283 5
337 11
320 12 T320N,