SCN5A Variant L395V Detail

We estimate the penetrance of LQTS for SCN5A L395V around 21% and the Brugada syndrome penetrance around 38%. SCN5A L395V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L395V is not present in gnomAD. L395V has been functionally characterized in 0 papers. This residue is located in a 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 (3 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 L395V around 21% (1/10) and the Brugada syndrome penetrance around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.621 56 26
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 11 1 3 - -
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.

L395V has 58 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 11
364 14
271 12 L271V,
266 13 L266H,
404 13 L404Q, L404V,
1627 12
396 5 V396A, V396L,
1624 11 V1624I,
355 14 F355C, F355I,
391 6
388 12 I388S,
401 11 S401P,
371 13 Q371E,
260 11
365 11
386 15 G386R, G386E,
369 11 M369K,
1767 14 Y1767C,
378 13
1654 13
402 11 F402L,
1630 15 I1630R, I1630V,
267 9
1625 14
262 13 S262G,
399 5
272 13
397 7 I397V, I397T, I397F,
1657 14
261 12
1709 15 T1709R, p.T1709del, T1709M,
1628 12
392 6
389 11 Y389X, Y389H,
1620 15 T1620K, T1620M,
395 0
393 8
390 9
394 5
264 7
259 14
382 15
265 12 A265V,
374 13 W374G,
1705 12
263 10 V263I,
1661 13 G1661R, G1661E,
381 14 c.1140+1G>A, c.1141-3C>A,
368 10
1631 14 G1631D,
268 11 G268S,
377 15
398 7
257 15
400 8 G400E, G400A, G400R,
1621 14
1664 14
1658 12