SCN5A Variant D356H Detail

We estimate the penetrance of LQTS for SCN5A D356H around 10% and the Brugada syndrome penetrance around 50%. SCN5A D356H was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. D356H is not present in gnomAD. D356H has been functionally characterized in 0 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 D356H around 10% (0/10) and the Brugada syndrome penetrance around 50% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.975 74 9
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 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.

D356H has 55 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
364 11
277 7
271 12 L271V,
266 11 L266H,
276 9 L276Q, L276P,
363 12
348 12 P348A,
270 10 Q270K,
360 7
279 15
1552 10 Q1552R, Q1552L,
355 7 F355C, F355I,
1549 6
278 13 H278D, H278R,
1556 15
356 0 D356N,
361 7
904 15 W904X,
343 11
365 13
384 15 S384T,
354 5
1546 12 M1546T,
1545 13
349 15 D349N,
267 13
1550 6
357 4
272 9
274 7 G274C,
362 12
273 6
1553 14 S1553R,
269 7
345 12
275 10 N275K,
912 15 Q912R,
347 9
1548 9 G1548K, E1548K,
351 10 G351S, G351C, G351D, G351V,
265 11 A265V,
350 15 H350Q,
358 9
1551 9 D1551N, D1551Y,
346 11 E346D, E346K, E346X, E346G,
359 8 p.A359PfsX12, A359T,
1547 11 V1547L,
344 12 A344S,
381 14 c.1141-3C>A, c.1140+1G>A,
352 10 Y352C,
380 15
268 9 G268S,
377 14
353 9 T353I,
1623 15 c.4867delC, R1623X, R1623Q, R1623L,