L618F Summary

SCN5A L618F was found in 7 papers (see below) with a total of 138 carriers: 1 had BrS1, 2 had LQT3, and 4 had other disease. L618F is present in 134 out of 223754 alleles in gnomAD (minor allele frequency of 0.059887%). L618F has been functionally characterized in 1 paper. Other variants at the same resdue are L618F .L618H .L618I .L618P .L618R .L618V . Given the functional data available, we estimate this variant has "Normal" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). This residue is located in a Non_Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

L618F Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
1199728120020001diLQT
1584047620050020
1984392120090100
2127319520110100
2463177520140002SD, SIDS
2516354620150001DCM
2012928320101000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

L618F 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
11997281 2002 HEK-tSA202 104.6 -4.9 3.9 NA

L618F 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 -2.18 possiblydamaging 0.748 1.563 -0.79 -3 0.676

L618F has 30 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
603 14.7
604 14.2 L604V
605 13.7
606 13.2
607 12.6 G607V
608 12 D608N
609 11.4
610 10.7
611 10.1
612 9.3
613 8.5
614 7.6
615 6.6 G615E
616 5.4
617 3.8
619 3.8 L619F
620 5.4 R620C R620H
621 6.6
622 7.6
623 8.5
624 9.3 L624Q
625 10.1 E625D E625D
626 10.7
627 11.4 P627L
628 12
629 12.6
630 13.2 T630M
631 13.7
632 14.2 T632M
633 14.7