L619F Summary

SCN5A L619F was found in 3 papers (see below) with a total of 12 carriers: 1 had BrS1, 2 had LQT3, and 0 had other disease. L619F is present in 9 out of 223308 alleles in gnomAD (minor allele frequency of 0.00403%). L619F has been functionally characterized in 1 paper. Other variants at the same resdue are L619F .L619H .L619I .L619P .L619R .L619V . 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 Mild_Hotspot region for Long QT syndrome.

L619F Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
1267379920030010
1499862420040010
2012928320100100
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

L619F 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
12673799 2003 HEK 83.1 -0.1 5.8 263.3

L619F 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 0.01 -2 possiblydamaging 0.82 2.619 -0.7 -3 0.726

L619F 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
604 14.7 L604V
605 14.2
606 13.7
607 13.2 G607V
608 12.6 D608N
609 12
610 11.4
611 10.7
612 10.1
613 9.3
614 8.5
615 7.6 G615E
616 6.6
617 5.4
618 3.8 L618F
620 3.8 R620C R620H
621 5.4
622 6.6
623 7.6
624 8.5 L624Q
625 9.3 E625D E625D
626 10.1
627 10.7 P627L
628 11.4
629 12
630 12.6 T630M
631 13.2
632 13.7 T632M
633 14.2
634 14.7 S634L