SCN5A Variant L271V Detail

We estimate the penetrance of LQTS for SCN5A L271V around 8% and the Brugada syndrome penetrance around 14%. SCN5A L271V was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L271V is present in 1 alleles in gnomAD. L271V 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 (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L271V around 8% (0/11) and the Brugada syndrome penetrance around 14% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.93 0.999 -0.42 0.921 14 11
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: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 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.

L271V has 66 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
328 15
364 13
277 14
271 0 L271V,
266 9 L266H,
276 11 L276P, L276Q,
387 15
270 6 Q270K,
1627 10
396 13 V396A, V396L,
385 9 A385T,
1624 8 V1624I,
355 8 F355I, F355C,
1549 14
391 11
278 13 H278R, H278D,
388 11 I388S,
356 12 D356N,
1542 14
361 11
343 14
365 13
384 11 S384T,
354 12
329 14
386 11 G386E, G386R,
1546 13 M1546T,
378 14
1545 11
1626 13 R1626H, R1626L, R1626C, R1626P,
267 6
1550 13
1625 12
262 14 S262G,
357 13
272 4
274 10 G274C,
273 8
1628 14
392 8
389 7 Y389X, Y389H,
269 7
1620 6 T1620M, T1620K,
395 12
393 11
394 14
390 13
275 8 N275K,
264 10
382 12
1548 12 E1548K, G1548K,
265 10 A265V,
1619 9 c.4856delC, P1619Q, P1619L,
358 13
263 12 V263I,
381 10 c.1141-3C>A, c.1140+1G>A,
1617 15 p.F1617del,
368 14
380 15
268 5 G268S,
377 14
1622 12
1618 11
1621 10
353 15 T353I,
1623 7 R1623L, R1623Q, R1623X, c.4867delC,