SCN5A Variant I723M Detail

We estimate the penetrance of LQTS for SCN5A I723M around 4% and the Brugada syndrome penetrance around 10%. SCN5A I723M was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I723M is not present in gnomAD. I723M has been functionally characterized in 0 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (0 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 I723M around 4% (0/10) and the Brugada syndrome penetrance around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.875 3 1
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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.

I723M has 54 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 6
723 0 I723V,
710 14
766 13
758 11 G758E,
733 15 F733L,
821 10
760 7 p.F760SfsX5,
776 15 p.Y776del,
721 7
765 13
759 8 I759V, p.I759FfsX6, c.2274delG,
764 9 M764K, M764R,
755 13
731 13 T731I,
819 13
726 5
818 10
781 13 W781X,
720 5
822 13 W822C, W822X,
788 12 I788V,
724 5 T724I,
782 13 N782T,
728 10 V728I,
820 10
713 12
762 10
727 6
767 10
717 11 P717L,
732 15
756 10
814 11 R814Q,
816 15 F816Y, F816L,
722 5
757 12
786 14
817 8 K817E,
761 11
752 14 G752R,
716 11
815 13
715 15 M715T, M715I,
725 7
784 13 F784L,
763 7 E763D, E763K,
785 10 D785N,
730 11 N730K,
789 13 V789A, V789I,
753 15
714 11 V714A, V714D,
729 10 p.L729del,
718 10 F718L,