SCN5A Variant F398V Detail

We estimate the penetrance of LQTS for SCN5A F398V around 31% and the Brugada syndrome penetrance around 25%. SCN5A F398V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F398V is not present in gnomAD. F398V 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 F398V around 31% (1/10) and the Brugada syndrome penetrance around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.955 29 39
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.

F398V has 62 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 7
1659 11
404 11 L404V, L404Q,
1765 13
396 8 V396A, V396L,
1653 12
391 11
1771 12 I1771T,
401 8 S401P,
1764 10 c.5290delG, V1764F,
1666 15
371 11 Q371E,
1650 12 L1650F,
260 13
1656 11
365 14
1704 14 L1704H,
1706 14 Q1706H,
1668 12 M1668T,
369 11 M369K,
1767 7 Y1767C,
1660 9 I1660V, I1660S,
378 14
1654 10
1769 14
402 5 F402L,
1766 13 M1766T, M1766V, M1766L,
1665 12
1768 12 I1768V,
1663 12
399 5
397 6 I397T, I397F, I397V,
405 12
1657 8
1759 13 S1759C,
1662 11
1709 11 p.T1709del, T1709R, T1709M,
1701 14 M1701I,
392 12
395 7
393 11
394 6
390 12
1770 12 I1770V,
264 12
1651 15
1708 11 T1708I,
374 13 W374G,
1705 10
407 14
1763 12 V1763M, V1763L,
1760 15
370 14 T370M,
1661 7 G1661R, G1661E,
1655 12
406 11 N406K, N406S,
368 12
398 0
400 7 G400E, G400R, G400A,
1667 14 V1667I,
1664 8
1658 8