D349N Summary

SCN5A D349N was found in 4 papers (see below) with a total of 9 carriers: 4 had BrS1, 0 had LQT3, and 1 had other disease. D349N is present in 4 out of 280338 alleles in gnomAD (minor allele frequency of 0.001427%). D349N has been functionally characterized in 1 paper. Other variants at the same resdue are D349A .D349E .D349E .D349G .D349H .D349N .D349V .D349Y . Given the functional data available, we estimate this variant has "Partial_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.

D349N Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2320027120131001SSS
2472145620140100
2970910120180300
3253394620200000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

D349N 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
32533946 2020 HEK 28.5 10.3 NA

D349N 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
Tolerated 1 0.39 probablydamaging 0.999 0.4999 5.17 2 0.442

D349N 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
274 14.7
276 10.5 L276Q
277 12.1
278 14.8
279 12.1
321 12.2
322 8.6
323 10.2
324 10.5
325 10.9
344 14.3
345 12.5
346 9.9 E346K
347 6.9
348 4.3
350 4.6
351 6.6 G351S G351V
352 8.5
353 6.3 T353I
354 10
355 13.5 F355I
356 14.6 D356N
360 12.4
361 14.9
363 12.9
364 12.2
367 11.4 R367C R367H
372 13.1
373 11
374 14.6
375 12.2
376 6.9 R376H
377 9.7
379 12.3
380 8.3
381 13
383 13.7
384 14.6
871 12.3
872 10.8 D872N
873 14.9
898 14.9
899 13.8
900 9.6
901 9.1 E901K
902 12.6
903 11.9
904 7.3
905 10.1
906 14.1
907 12.3
908 10.6
909 14.9
912 14.7 Q912R