SCN5A Variant Q371H Detail

We estimate the penetrance of LQTS for SCN5A Q371H around 35% and the Brugada syndrome penetrance around 19%. SCN5A Q371H was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Q371H is not present in gnomAD. Q371H has been functionally characterized in 0 papers. This residue is located in a Mild_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 Q371H around 35% (1/10) and the Brugada syndrome penetrance around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.889 19 45
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 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.

Q371H has 75 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
403 13
364 11
363 14
896 13 C896S,
404 11 L404V, L404Q,
895 15 L895F,
1417 12
1765 13
396 9 V396L, V396A,
894 14 I894M,
372 6
401 6 S401P,
1764 11 V1764F, c.5290delG,
371 0 Q371E,
409 15 L409P, L409V,
1711 8 c.5131delG,
928 12 L928P,
366 10
1707 12
365 11
1704 15 L1704H,
1706 10 Q1706H,
376 13 R376H, R376C,
897 9 G897E, G897R,
924 15 V924I,
927 12 N927S, N927K,
369 7 M369K,
1767 13 Y1767C,
378 12
1418 12
402 8 F402L,
373 8
1768 13 I1768V,
1712 12 G1712C, G1712S,
379 15
898 11
893 14 R893C, R893H,
399 13
397 6 I397F, I397T, I397V,
405 9
1759 13 S1759C,
261 14
920 15
1709 6 T1709R, p.T1709del, T1709M,
900 12
392 13
395 13
393 10
1713 13
394 12
264 14
1708 10 T1708I,
408 14
374 6 W374G,
1705 12
407 15
367 8 R367C, R367H, R367L,
1763 15 V1763M, V1763L,
1760 11
370 5 T370M,
1761 15 L1761H, L1761F, c.5280delG,
923 12
375 10
406 11 N406S, N406K,
368 6
899 10
1710 8 S1710L,
377 11
932 14
398 11
257 15
400 9 G400R, G400A, G400E,
1419 11 K1419E,
931 15
1664 14