SCN5A Variant D372Y Detail

We estimate the penetrance of LQTS for SCN5A D372Y around 26% and the Brugada syndrome penetrance around 29%. SCN5A D372Y was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. D372Y is not present in gnomAD. D372Y has been functionally characterized in 0 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 (2 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 D372Y around 26% (1/10) and the Brugada syndrome penetrance around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.968 38 33
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 12 1 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.

D372Y has 72 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 9
891 14 I891N, I891T,
890 14 I890T,
919 12
901 9 S901L, E901K,
363 10
896 11 C896S,
895 12 L895F,
1417 13
396 13 V396A, V396L,
894 9 I894M,
355 15 F355C, F355I,
372 0
401 11 S401P,
926 15
371 6 Q371E,
1711 10 c.5131delG,
928 13 L928P,
361 14
904 11 W904X,
366 9
365 11
1706 12 Q1706H,
376 10 R376C, R376H,
897 6 G897R, G897E,
924 14 V924I,
927 12 N927K, N927S,
369 10 M369K,
1422 13 M1422R,
378 13
1418 11
902 10
402 14 F402L,
892 15 F892I,
349 13 D349N,
373 4
1712 12 G1712C, G1712S,
379 14
898 6
893 9 R893H, R893C,
922 13 V922I,
397 11 I397V, I397T, I397F,
405 13
362 14
261 15
920 12
1709 11 T1709R, T1709M, p.T1709del,
1420 13 G1420D, G1420P, G1420R, G1420V,
900 6
393 13
1713 14
916 14
1708 15 T1708I,
1421 12
374 8 W374G,
350 14 H350Q,
903 10 p.M903CfsX29,
367 4 R367C, R367H, R367L,
1760 15
370 6 T370M,
923 9
905 14
375 9
368 8
899 5
1710 11 S1710L,
380 14
377 9
400 14 G400E, G400R, G400A,
1419 10 K1419E,
353 12 T353I,
907 15