SCN5A Variant p.Y776del Detail

We estimate the penetrance of LQTS for SCN5A p.Y776del around 14% and the Brugada syndrome penetrance around 54%. SCN5A p.Y776del was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. p.Y776del is not present in gnomAD. p.Y776del has been functionally characterized in 1 papers. This residue is located in a Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (4 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A p.Y776del around 14% (0/11) and the Brugada syndrome penetrance around 54% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 75 19
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are 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. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 0 4 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from 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.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
20129283 2010

p.Y776del has 41 previously observed neighbors within 15 angstroms

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. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
719 15
723 15 I723V,
710 13
766 11
715 14 M715I, M715T,
820 14
713 14
762 13
774 9 Y774C, p.Y774TfsX28, Y774D, c.2320delT,
784 11 F784L,
763 11 E763D, E763K,
778 8
767 6
772 7 D772N,
770 8
781 11 W781X,
775 8
771 6 L771V,
720 13
785 8 D785N,
783 7 I783T,
769 9
789 12 V789I, V789A,
773 6 P773S,
760 14 p.F760SfsX5,
714 11 V714A, V714D,
780 9
776 0 p.Y776del,
788 13 I788V,
768 5
765 10
786 8
817 13 K817E,
761 13
711 12
787 11
779 7 Q779K, Q779X,
764 7 M764K, M764R,
777 4 F777L,
782 4 N782T,
790 13