SCN5A Variant R282H Detail

We estimate the penetrance of LQTS for SCN5A R282H around 1% and the Brugada syndrome penetrance around 46%. SCN5A R282H was found in a total of 8 carriers in 6 papers and/or in gnomAD: 4 had Brugada syndrome, 0 had LQTS. R282H is present in 4 alleles in gnomAD. R282H has been functionally characterized in 9 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 R282H around 1% (0/18) and the Brugada syndrome penetrance around 46% (8/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.53 1 -0.88 0.794 54 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
15828879 2005 3 0 3 0
11901046 2002 1 0 1 0
20219395 2011 1 0 1 0
20625312 2010 1 0 1 0
28341781 2017 3 0 3 0
29574140 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 8 4 0 4 -
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)
15828879 2005 HEK 12 5 5.3
29574140 2018
11901046 2002
20219395 2011
20625312 2010
28341781 2017
16880338 2006
21840964 2011 HEK 3
16864729 2006 HEK 0

R282H has 27 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
287 12
341 12 C341Y,
342 11
326 13
335 11 C335R, C335S,
339 5
319 8 G319S, G319R, G319C,
317 14 K317E, K317N, K317M,
284 6
336 9 P336L,
282 0 R282C, R282H,
279 12
324 14
321 11 S321Y,
344 14 A344S,
340 9 R340W, R340Q,
285 6 T285K,
338 6
322 14
280 8 C280Y,
318 12
281 6 V281M,
323 11
283 6
337 10
286 8 A286S, A286V,
320 9 T320N,