R376H Summary

SCN5A R376H was found in 8 papers (see below) with a total of 15 carriers: 7 had BrS1, 0 had LQT3, and 1 had other disease. R376H is present in 2 out of 247596 alleles in gnomAD (minor allele frequency of 0.000808%). R376H has been functionally characterized in 2 papers. Other variants at the same resdue are R376C .R376G .R376H .R376L .R376P .R376S . 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 Mild_Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

R376H Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
1634440020050100
1585122820046301Conduction Defects
2834178120170100
2012928320100100
2012928320100100
2012928320100100
2932597620180200
2970910120186600
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

R376H 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
16344400 2005 HEK 7.2 NA
15851228 2004 HEK 30 1.7 3.1 NA

R376H 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 0.009 -1.54 probablydamaging 1 1.172 -2.45 -2 0.738

R376H has 65 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
276 11.3 L276Q
279 15
322 12.9
323 12.7
324 10.4
325 10.6
347 11.8
348 8.4
349 6.9 D349N
350 10.7
351 12.4 G351S G351V
352 13.8
353 8.9 T353I
354 12.5
355 13.8 F355I
363 14
364 11.7
367 9.3 R367C R367H
368 12.1
370 14.6 T370M
371 13.5 Q371E
372 9.8
373 6.5
374 8.9
375 5.4
377 6.1
378 9.5
379 6.4
380 5.7
381 10.1
382 11.7
383 10.8
384 13.2
393 12.9
893 14.6 R893C R893H
897 14.9
898 12.3
899 13
900 9.8
901 9.7 E901K
902 14.1
903 14.2
904 11
905 14
1419 12.2
1420 13.4 G1420R G1420V
1422 14.7
1423 14.6
1686 11.9
1687 10.4
1688 13.7
1689 12
1691 13.8
1692 11.8
1702 14.5
1703 14
1706 10.7
1709 14.4 T1709M
1710 14.3 S1710L
1711 10.6
1712 10.3 G1712S
1713 15
1714 13.8
1715 11.9
1716 13.2