SCN5A Variant A332T Detail

We estimate the penetrance of LQTS for SCN5A A332T around 27% and the Brugada syndrome penetrance around 15%. SCN5A A332T was found in a total of 3 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. A332T is present in 2 alleles in gnomAD. A332T has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_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 A332T around 27% (2/13) and the Brugada syndrome penetrance around 15% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.13 0.271 -0.15 0.681 25 30
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
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 2 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)
30059973 2018

A332T has 49 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
328 7
333 3 c.998+5G>A, c.998+1G>A,
1702 11
326 7
276 13 L276Q, L276P,
387 7
279 14
385 6 A385T,
330 6 S330F,
278 11 H278R, H278D,
388 9 I388S,
1698 12 A1698T,
334 5 c.999-424_1338+81del,
332 0 A332T,
327 6
1695 15 Q1695X,
384 6 S384T,
1688 15
329 4
1692 10
386 5 G386E, G386R,
1693 12
378 12
1699 11
331 5
379 11
1703 15
272 14
341 11 C341Y,
335 9 C335R, C335S,
325 9 L325R,
1690 11 D1690N, c.5068_5070delGA,
324 12
1697 15
389 10 Y389H, Y389X,
393 15
390 13
275 12 N275K,
383 6
280 12 C280Y,
323 15
382 7
1696 13
1689 10 D1689N,
342 15
336 12 P336L,
381 9 c.1141-3C>A, c.1140+1G>A,
1691 7
380 12