SCN5A Variant G345A Detail

We estimate the penetrance of LQTS for SCN5A G345A around 7% and the Brugada syndrome penetrance around 23%. SCN5A G345A was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. G345A is not present in gnomAD. G345A has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 G345A around 7% (0/10) and the Brugada syndrome penetrance around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.894 27 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: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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.

G345A has 43 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
277 6
326 14
276 11 L276Q, L276P,
348 9 P348A,
317 8 K317E, K317M, K317N,
360 15
279 6
1549 15
278 10 H278D, H278R,
356 12 D356N,
318 12
343 8
327 15
384 14 S384T,
354 11
340 14 R340Q, R340W,
349 13 D349N,
1550 11
357 15
341 12 C341Y,
274 10 G274C,
273 14
319 11 G319S, G319C, G319R,
325 12 L325R,
324 13
321 8 S321Y,
345 0
275 12 N275K,
280 12 C280Y,
323 10
347 7
351 9 G351S, G351D, G351C, G351V,
320 8 T320N,
350 13 H350Q,
342 9
1551 12 D1551N, D1551Y,
346 4 E346X, E346K, E346G, E346D,
344 3 A344S,
322 10
352 12 Y352C,
380 14
281 10 V281M,
353 12 T353I,