SCN5A Variant L399V Detail

We estimate the penetrance of LQTS for SCN5A L399V around 22% and the Brugada syndrome penetrance around 20%. SCN5A L399V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L399V is not present in gnomAD. L399V 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 L399V around 22% (1/10) and the Brugada syndrome penetrance around 20% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.781 23 27
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.

L399V has 64 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 6
1659 14
404 9 L404V, L404Q,
396 7 V396L, V396A,
1624 15 V1624I,
1653 12
391 11
1771 12 I1771T,
401 8 S401P,
1634 14 L1634P,
1764 14 V1764F, c.5290delG,
371 13 Q371E,
1650 10 L1650F,
260 9
366 15
1656 13
365 12
369 10 M369K,
1767 10 Y1767C,
1660 12 I1660S, I1660V,
1654 9
402 7 F402L,
1630 15 I1630V, I1630R,
1649 14 A1649V,
1768 14 I1768V,
267 13
262 14 S262G,
256 13
399 0
397 7 I397V, I397T, I397F,
405 12
1657 9
261 12
1662 14
1709 14 T1709M, p.T1709del, T1709R,
1628 13
392 10
395 5
393 11
390 13
394 8
1770 14 I1770V,
264 9
1651 12
1708 15 T1708I,
259 13
265 14 A265V,
374 14 W374G,
1705 14
407 13
263 11 V263I,
370 14 T370M,
1661 11 G1661R, G1661E,
1655 12
1631 13 G1631D,
406 12 N406K, N406S,
368 11
398 5
1647 13
257 13
400 5 G400E, G400A, G400R,
1646 15
1664 13
1658 9