SCN5A Variant Y389N Detail

We estimate the penetrance of LQTS for SCN5A Y389N around 5% and the Brugada syndrome penetrance around 15%. SCN5A Y389N was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Y389N is not present in gnomAD. Y389N has been functionally characterized in 0 papers. This residue is located in a Mild_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 Y389N around 5% (0/10) and the Brugada syndrome penetrance around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.953 12 2
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 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.

Y389N 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
328 12
333 13 c.998+5G>A, c.998+1G>A,
271 7 L271V,
1702 11
266 15 L266H,
326 15
276 11 L276Q, L276P,
387 8
270 13 Q270K,
396 12 V396L, V396A,
385 6 A385T,
1624 12 V1624I,
355 11 F355I, F355C,
391 7
330 11 S330F,
278 13 H278D, H278R,
388 4 I388S,
1698 13 A1698T,
332 10 A332T,
365 14
327 12
384 9 S384T,
354 15
329 10
1692 14
386 5 G386E, G386R,
378 9
1699 14
331 12
267 11
379 13
272 7
397 14 I397V, I397F, I397T,
274 13 G274C,
273 13
1701 14 M1701I,
325 14 L325R,
392 7
389 0 Y389X, Y389H,
269 13
1620 10 T1620K, T1620M,
395 11
393 8
394 11
390 7
275 10 N275K,
383 12
264 13
382 7
265 14 A265V,
1619 13 P1619Q, c.4856delC, P1619L,
374 14 W374G,
1705 13
381 7 c.1140+1G>A, c.1141-3C>A,
1691 13
368 14
380 12
268 10 G268S,
377 12
1618 14
1621 11
1623 13 R1623L, R1623X, c.4867delC, R1623Q,