P648L Summary

SCN5A P648L was found in 7 papers (see below) with a total of 17 carriers: 1 had BrS1, 2 had LQT3, and 2 had other disease. P648L is present in 14 out of 279340 alleles in gnomAD (minor allele frequency of 0.005012%). P648L has been functionally characterized in 0 papers. Other variants at the same resdue are P648A .P648L .P648Q .P648R .P648S .P648T . 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 Mild_Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

P648L Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2461399520140001irritable bowel syndrome
1584047620050010
1941232820080001DCM
2363143020130010
2694133920160100
2590454120150010
2012928320100100
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

P648L 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
24613995 2014 HEK 98.7 2 -0.5 45.1

P648L 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
Tolerated 1 0.47 benign 0.011 3.754 -0.49 -7 0.485

P648L 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
633 14.7
634 14.2 S634L
635 13.7
636 13.2
637 12.6
638 12
639 11.4 G639R G639R
640 10.7 P640A
641 10.1
642 9.3
643 8.5
644 7.6
645 6.6
646 5.4
647 3.8 A647D A647S A647V
649 3.8 C649Y
650 5.4
651 6.6
652 7.6
653 8.5
654 9.3 E654K
655 10.1 E655K
656 10.7 P656L
657 11.4
658 12
659 12.6 R659Q R659W
660 13.2
661 13.7 R661W
662 14.2 A662S
663 14.7