D356N Summary

SCN5A D356N was found in 10 papers (see below) with a total of 10 carriers: 9 had BrS1, 0 had LQT3, and 0 had other disease. D356N is present in 1 out of 249040 alleles in gnomAD (minor allele frequency of 0.000402%). D356N has been functionally characterized in 1 paper. Other variants at the same resdue are D356A .D356E .D356E .D356G .D356H .D356N .D356V .D356Y . Given the functional data available, we estimate this variant has "LOF" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). This residue is located in a Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

D356N Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
1632504820050100
2288591720120200
2617311120150100
2012928520100000
2018823020100000
2012928320100800
2932597620180200
2932597620180200
2957414020180100
3005997320180030
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

D356N Reported Functional Data

Peak current and late current are relative % to wildtype. V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.

PMID Year Cell type Peak current V0.5 act V0.5 inact Rec from inact Late current
16325048 2005 HEK NA NA

D356N Predictions

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 is 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. PAM scores reflect the chemistry difference between WT and variant amino acid (more negative being greater difference between the two). BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected.

SIFT Sift Score PROVEAN Score Polyphen2 Polyphen2 Score eaRate blastPssm pamScore REVEL
Damaging 0 -4.91 probablydamaging 1 0.07709 -1.11 2 0.961

D356N has 54 neighbors within 15 ångströms that have been found in individuals.

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.

ResidueNumber Distance(Å) Variants
265 10.7
266 11.3
267 13
268 9.2
269 6.5
270 9.9 Q270K
271 11.7
272 9.5
273 5.8
274 6.7
275 9.6
276 8.9 L276Q
277 7.5
278 12.6
279 14.5
343 10.6
344 12.2
345 11.6
346 11 E346K
347 9
348 11.8
349 14.6 D349N
350 14.9
351 9.7 G351S G351V
352 10.1
353 9.1 T353I
354 5.2
355 6.6 F355I
357 4
358 8.7
359 8.1
360 7.3
361 7.4
362 12.2
363 11.6
364 11.1
365 13.2
377 14
380 14.7
381 13.8
384 14.6
904 14.5
912 14.6 Q912R
1545 13.4
1546 11.7
1547 11.1
1548 9.3 E1548K G1548K
1549 6.1
1550 5.7
1551 9.4 D1551N
1552 10.2
1553 14.1
1556 14.8
1623 14.8 R1623L R1623Q