R367H Summary

SCN5A R367H was found in 19 papers (see below) with a total of 16 carriers: 13 had BrS1, 0 had LQT3, and 6 had other disease. R367H is not present in gnomAD. R367H has been functionally characterized in 4 papers. Other variants at the same resdue are R367C .R367G .R367H .R367L .R367P .R367S . 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 Mild_Hotspot region for Long QT syndrome.

R367H Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
1502807420042900
1468725020041101 atrial standstill
2202845720110001VF
1182345320020001SUNDS
2902469020170100
1502807520040000
1552032220042600
1769782320070200
2289977520120002Conduction defects
2617311120150100
2834178120170100
1925120920090100
2452977320140001SUNDS
2012928320100100
2012928320100100
2012928320100100
2012928320100100
2970910120180100
3005997320180010
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

R367H 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
15028074 2004 HEK NA NA
14687250 2004 HEK-tSA201 NA NA
22028457 2011 HEK-tSA201 NA NA
11823453 2002 Xeno NA NA
29024690 2017 hiPSC 54.5 7.42 -8.51 50

R367H 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 0.1234 -3.14 -2 0.972

R367H has 74 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
261 11.9
264 13.5
265 12.5
268 13.3
272 14
276 13.2 L276Q
347 13.9
348 12.6
349 11.4 D349N
350 12.5
351 13 G351S G351V
352 12
353 8.7 T353I
354 11
355 10.5 F355I
358 14.7
359 12.8
360 11.3
361 9.9
362 10.2
363 6.5
364 4.7
365 7.3
366 6.7
368 5.5
369 9 M369K
370 6.7 T370M
371 8.2 Q371E
372 4.5
373 6.1
374 7.6
375 10.1
376 9.3 R376H
377 6.4
378 11.7
379 12.9
380 11.6
381 12.4
392 12.8
393 10.8
396 10.8
397 10.8 I397V
400 13.4 G400E G400R G400R
401 11.5
402 14.9 F402L F402L F402L
404 15
405 14.3
893 12.9 R893C R893H
894 12.4
896 14.8
897 10.1
898 10.1
899 6.4
900 5.8
901 10.5 E901K
902 11.9
903 9.4
904 9
905 14.2
907 13.2
915 14.9
916 12
919 12.7
920 11.3
922 14.9
923 11.3
927 14.5 N927S
928 14.9
1419 13.7
1706 13.3
1709 12.7 T1709M
1710 13.9 S1710L
1711 12.1
1712 14.3 G1712S