SCN5A Variant L266H Detail

We estimate the penetrance of LQTS for SCN5A L266H around 3% and the Brugada syndrome penetrance around 11%. SCN5A L266H was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L266H is present in 1 alleles in gnomAD. L266H has been functionally characterized in 0 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Non_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 L266H around 3% (0/11) and the Brugada syndrome penetrance around 11% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.83 1 -6.07 0.983 2 4
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.

L266H 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
364 12
271 9 L271V,
266 0 L266H,
363 14
1544 10 T1544P,
270 6 Q270K,
360 14
1627 7
396 13 V396A, V396L,
1624 9 V1624I,
355 9 F355I, F355C,
1549 12
1538 12
356 11 D356N,
1543 9 V1543L, V1543A,
1542 6
361 8
260 11
366 15
365 10
1564 14
258 12 V258A,
354 13
1546 5 M1546T,
1545 6
1630 11 I1630V, I1630R,
1626 10 R1626H, R1626L, R1626C, R1626P,
267 5
1550 14
1625 13
1560 14 L1560F,
262 6 S262G,
357 10
272 10
274 14 G274C,
362 10
261 10
273 10
1628 11
1539 12 C1539F, C1539Y,
392 11
389 15 Y389X, Y389H,
269 5
1620 12 T1620M, T1620K,
395 13
393 15
275 14 N275K,
264 8
259 11
1548 9 E1548K, G1548K,
265 4 A265V,
1619 14 c.4856delC, P1619Q, P1619L,
358 7
263 6 V263I,
359 11 A359T, p.A359PfsX12,
1629 13 R1629X, R1629G, R1629Q,
1547 10 V1547L,
1541 10
1540 13
1631 14 G1631D,
368 14
268 6 G268S,
1622 13
257 15
1621 14
1623 9 R1623L, R1623Q, R1623X, c.4867delC,