C335R Summary

SCN5A C335R was found in 3 papers (see below) with a total of 2 carriers: 2 had BrS1, 0 had LQT3, and 1 had other disease. C335R is not present in gnomAD. C335R has been functionally characterized in 1 paper. Other variants at the same resdue are C335F .C335G .C335R .C335S .C335S .C335W .C335Y . 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.

C335R Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2878133020170100
2940234020170101atrial flutter
3253394620200000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

C335R 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 NA NA

C335R 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 -11.77 probablydamaging 0.998 0.4756 -2.44 -8 0.957

C335R has 34 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
278 11.2
279 11.5
280 6.7
281 9.8 V281M
282 11.3 R282C R282H
283 12
284 14.7
323 11.9
324 10.7
325 10.3
326 5.3
327 6.5
328 8.4
329 10.5
330 12.4
331 12.3
332 9.1 A332T
333 7.2
334 4.1
336 3.7 P336L
337 7.7
338 7.7
339 6.5
340 9 R340Q R340W
341 7.6 C341Y
342 11
382 14.7
383 9.7
384 11
385 13.2 A385T
386 14.2 G386E G386R G386R
1689 12.6
1690 11.8 D1690N
1691 12.1